Thienopyridone derivatives as AMP-activated protein kinase (AMPK) activators

ABSTRACT

The present invention relates to compounds of formula (I) wherein R1, R2 and R3 are as defined in claim  1 , including pharmaceutical compositions thereof and for their use in the treatment and/or prevention of diseases and disorders modulated by AMP agonists. The invention is also directed to intermediates and to a method of preparation of compounds of formula (I).

FIELD OF THE INVENTION

The invention relates to thienopyridone derivatives that are activatorsof AMPK-activated protein kinase (AMPK) of formula (I).

The invention also relates to the preparation and use of thesethienopyridones in the treatment of disorders such as diabetes,metabolic syndrome, obesity, cancer, inflammation.

BACKGROUND OF THE INVENTION

The invention had the object of finding novel compounds having valuableproperties, in particular those which can be used for the preparation ofmedicaments.

The present invention relates to compounds that are useful in thetreatment and/or prevention of diseases such as diabetes, metabolicsyndrome, obesity, cancer, inflammation.

Also provided are methods of treating diseases and disorders which canbe treated by activating AMPK, comprising administering an effectiveamount of a compound of this invention.

The present invention therefore relates to compounds according to theinvention as medicaments and/or medicament active ingredients in thetreatment and/or prophylaxis of the said diseases and to the use ofcompounds according to the invention for the preparation of apharmaceutical for the treatment and/or prophylaxis of the said diseasesand also to a process for the treatment of the said diseases whichcomprises the administration of one or more compounds according to theinvention to a patient in need of such an administration.

Surprisingly we have found that thienopyridone derivatives activateAMPK; therefore, these compounds are especially suitable for theprevention and treatment of diabetes, metabolic syndrome, obesity,cancer, inflammation. It has been found that the compounds according tothe invention and salts thereof have very valuable pharmacologicalproperties while being well tolerated. In particular, they exhibit AMPKactivating effects.

The host or patient may belong to any mammal species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, where they provide a model forthe treatment of a human disease.

AMPK is well established as a sensor and regulator of cellular energyhomeostasis (Hardie D. G. and Hawley S. A; “AMP-activated proteinkinase: the energy charge hypothesis revisited” Bioassays, 23, 1112,(2001), Kemp B. E. et al. “AMP-activated protein kinase, super metabolicregulator”, Biochem; Soc. Transactions, 31, 162 (2003)), Allostericactivation of this kinase due to rising AMP levels occurs in states ofcellular energy depletion. The resulting serine/Threoninephosphorylation of target enzymes leads to an adaptation of cellularmetabolism to low energy state. The net effect of AMPK activationinduced changes is inhibition of ATP consuming processes and activationof ATP generating pathways, and therefore regeneration of ATP stores.Examples of AMPK substrates include acetyl-CoA carboxylase (ACC) andHMG-CoA-reductase (Carling D. et al., “A commun bicyclic protein kinasecascade inactivates the regulatory enzymes of fatty acid and cholesterolbiosynthesis”, FEBS letters, 223, 217 (1987)). Phosphorylation andtherefore inhibition of ACC leads to a decrease in fatty acid synthesis(ATP-consuming) and at the same time to an increase in fatty acidoxidation (ATP-generating). Phosphorylation and resulting inhibition ofHMG-CoA-reductase leads to a decrease in cholesterol synthesis. Othersubstrates of AMPK include hormone sensitive lipase (Garton A. J. et al.phosphorylation of bovine hormone-sensitive lipase by AMP-activatedprotein kinase; A possible antilipolytic mechanism”, Eur. J. Biochem.179, 249, (1989)), glycerol-3-phosphate acyltransferase (Muoio D. M. etal. “AMP-activated kinase reciprocally regulates triacylglycerolsynthesis and fatty acid oxidation in liver and muscle: evidence thatsn-glycerol-3-phosphate acyltranferase is a novel target”, Biochem. J.,338, 783, (1999)), malonyl-CoA decarboxylase (Sarah A. K. et al.,“activation of malonyl-CoA decarboxylase in rat skeletal muscle bycontraction and the AMP-activated protein kinase activator5-aminoimidazole-4-caboxamide-1-β-D-ribofuranoside”, J. Biol. Chem.,275, 24279, (2000)).

AMPK is also implicated in the regulation of liver metabolism. Elevatedglucose production by the liver is a major cause of fastinghyperglycemia in T2D (Said et al., “new perspectives into the molecularpathogenesis and treatment of type 2 diabetes, cell 10, 517-529 (2001)).Gluconeogenesis in the liver is regulated by multiple enzymes such asphosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase-G6Pase). Activation of AMPK suppresses the transcription of theses genesin hepatoma, cells (Lochhead et al, “5-aminoimidazole-4-carboxamideriboside mimics the effects of insulin on the expression of the 2 keygluconeogenic genes PEPCK and glucose-6-phosphatase, Diabetes, 49,896-903 (2000))

AMPK activation also down-regulates gluconeogenesis acting on some othergenes expression. These effects may be due to its ability todown-regulate key transcription factors such as SREBP-1c (Zhou G. etal., “Role of AMP-activated protein kinase in mechanism of metforminaction” J. Clin. Invest, 108, 1167 (2001)) ChREBP (Kawaguchi T. et al.,“mechanism for fatty acids sparing effect on glucose inducedtranscription: regulation of carbohydrate response element bindingprotein by AMP-activated protein kinase” J. Biol. Chem. 277, 3829involved in (Leclerc I. et al., “Hepatocyte nuclear factor-4□(2001)) orHNF-4 type 1 maturity-onset diabetes of the young is a novel target ofAMP-activated protein kinase” Diabetes, 50, 1515 (2001)) or by directphosphorylation of transcriptional coactivators such as p300 (Yang W; etal., “Regulation of transcription by AMP-activated protein kinase;Phosphorylation of p300 blocks its interaction with nuclear receptors”J. Biol. Chem. 276, 38341 (2001)) and TORC2.

AMPK is considered as an attractive candidate for contraction-inducedskeletal muscle glucose uptake because it is activated in parallel withelevation in AMP and a reduction in creatine phosphate energy stores(Hutber et al. “Electrical stimulation inactivates muscle acetyl-CoAcarboxylase and increases AMP-activated protein kinase” Am. J. Physiol.Endocrinol, Metab. 272, E262-E66 (1997)). Furthermore, AICAR-inducedactivation of AMPK increases glucose uptake (Merrill et al. “AICARiboside increases AMP-activated protein kinase, fatty acid oxidationand glucose uptake in rat muscle” Am. J. Physiol. Endocrinol. Metab.273, E1107-E1112 (1997)) concomitantly with glucose transporter 4(GLUT4) fusion with plasma membrane (Kurth-Kraczek “5′-AMP-activatedprotein kinase activation causes GLUT4 translocation in skeletal muscle,Diabetes, 48, 2□1667-1671 (1999)). Over expression of an kinase deadsubunit in skeletal muscle abolishes AICAR, but partially impairscontraction-stimulated glucose uptake (Mu J. et al. “A role forAMP-activated protein kinase in contraction and hypoxia-regulatedglucose transport in skeletal muscle, Mol. Cell. 7, 1085-1094 (2001)).These findings suggest that additional pathways mediate contractioninduced glucose uptake whereas it is apparent that AMPK mediates theeffects of AICAR on glucose uptake.

Despite extensive study on upstream stimuli that activate AMPK,investigation on the downstream substrate(s) of AMPK-mediated glucoseuptake is lacking. More recent reports revealed that Akt substrate of160 kDa (AS160) is an important substrate downstream of Akt that isinvolved in insulin-stimulated glucose uptake. In addition to insulin,contraction and activation of AMPK by AICAR is associated with increasedphosphorylation of AS160 in rodent skeletal muscle. Phosphorylation ofAS160 is impaired or abolished in skeletal muscle from AMPK a2 knockout,g3 knockout, and a2-kinase dead mice in response to AICAR treatment(Treeback et al. AMPK-mediated AS160 phosphorylation in skeletal muscleis dependent on AMPK catalytic and regulatory subunits, Diabetes(2006)). This coroborates findings of impaired AICAR-stimulated glucoseuptake in skeletal muscle of these mice (Jorgensen S. B. et al. Knockoutof the a2 but not a1 5′-AMP-activated protein kinase isoform abolishes5-aminoimidazole-4-carboxamide-1b-4 ribofuranoside but notcontraction-induced glucose uptake in skeletal muscle, J. Biol. Chem.279, 1070-1079 (2004)). Therefore, AS160 appeared to be a downstreamtarget of AMPK in mediating glucose uptake in skeletal muscle.

Taken together all these metabolic effects provide evidence that AMPKsuppresses liver gluconeogenesis and lipid production, while decreasinghepatic lipid deposition via increased lipid oxidation, thus improvingthe glucose and lipid profile in T2D.

More recently an involvement of AMPK in the regulation of not onlycellular but also whole body energy metabolism has become apparent. Itwas shown that the adipocyte-derived hormone leptin leads to astimulation of AMPK and therefore to an increase in fatty acid oxidationin skeletal muscle (Minokoshi Y. et al, “leptin stimulates fatty-acidoxidation by activating AMP activated protein kinase”, Nature, 415, 339(2002)). Adiponectin another adipocyte derived hormone leading toimproved carbohydrate and lipid metabolism, has been demonstrated tostimulated AMPK liver and skeletal muscle (Yamanauchi T. et al,“adiponectin stimulates glucose utilization and fatty acid oxidation byactivating AMP-activated protein kinase”, Nature Medicine, 8, 1288,(2002)), Tomas E. et al., “Enhanced muscle fat oxidation and glucosetransport by ACRP30 globular domain: Acetyl-CoA carboxylase inhibitionand AMP-activated protein kinase activation” PNAS, 99, 16309, (2002)).The activation of AMPK in these circumstances seems to be independent ofincreasing cellular AMP levels but rather due to phosphorylation by oneor more yet to be identified upstream kinases.

Based on the knowledge of the above-mentioned consequences of AMPKactivation, profound beneficial effects would be expected from in vivoactivation of AMPK. In liver, decreased expression gluconeogenic enzymeswould reduce hepatic glucose output and improve overall glucosehomeostasis, and both direct inhibition and/or reduced expression of keyenzymes in lipid metabolism would increase glucose uptake and fatty acidoxidation with resulting improvement of glucose homeostasis and, due toa reduction in intra-myocyte triglyceride accumulation, to improvedinsulin action. Finally, the increase in energy expenditure should leadto a decrease in body weight. The combination of these effects in themetabolic syndrome would be expected to significantly reduce the riskfor acquiring cardiovascular diseases.

Several studies in rodents support this hypothesis (Bergeron R. et al.“Effect of 5-aminoimidazole-4-carboxamide-1(beta)-D-rifuranosideinfusion on in vivo glucose metabolism in lean and obese Zucker rats”,Diabetes, 50, 1076 (2001), Song S. M. et al.,5-aminoimidazole-4-dicarboxamide ribonucleoside treatment improvesglucose homeostasis in insulin-resistant diabeted (ob/ob) mice”,Diabetologia, 45, 56 (2002), Halseth A. E. et al., “Acute and chronictreatment of ob/ob and db/db mice with AICAR decreases blood glucoseconcentration”, Biochem. and Biophys. Res. Comm., 294, 798 (2002), BuhlE. S. et al., “Long-term AICAR administration reduces metabolicdisturbances and lowers blood pressure in rats displaying feature of theinsulin resistance syndrome”, Diabetes, 51, 2199 (2002)). Until recentlymost in vivo studies have relied on the AMPK activator AICAR, a cellpermeable precursor of ZMP. ZMP acts as an intracellular AMP mimic and,when accumulated to high enough levels, is able to stimulate AMPKactivity (Corton J. M. et al. “5-aminoimidazole-4-dicarboxamideribonucleoside, a specific method for activating AMP-activated proteinkinase in intact cells?”, Eur. J. Biochem., 229, 558 (1995)). However,ZMP also acts as an AMP mimic in the regulation of other enzymes, andtherefore not a specific AMPK activator (Musi N. and Goodyear L. J.,“Targeting the AMP-activated protein kinase for the treatment of type 2diabetes”, Current Drug Targets-immune, Endocrine and MetabolicDisorders, 2 119 (2002)). Several in vivo studies have demonstratedbeneficial effects of both acute and chronic AICAR administration inrodent models of obesity and type 2 diabetes (Bergeron R. et al.,“Effect of 5-aminoimidazole-4-carboximide-1b-D ribofuranoside infusionon in vivo glucose metabolism in lean and obese Zucker rats”, Diabetes,50, 1076, (2001), Song S. M. et al., “5-aminoimidazole-4-carboxamideribonucleotide treatment improves glucose homeostasis in insulinresistant diabetic (ob/bo) mice”, Diabetologia, 45, 56, (2002), HalsethA. E. et al., “Acute and chronic treatment of ob/ob and db/db mice withAICAR decreases blood glucose concentrations” Biochem. Biophys. Res.Comm. 294, 798, (2002), Buhl E. S, et al., “Long-term AICARadministration reduces metabolic disturbances and lowers blood pressurein rats displaying feature of the insulin resistance syndrome”,Diabetes, 51, 2199 (2002)). For example, 7 week AICAR administration inthe obese Zucker (fa/fa) rat leads to a reduction in plasmatriglycerides and free fatty acids, an increase in HDL cholesterol, anda normalisation of glucose metabolism as assessed by an oral glucosetolerance test (Minokoshi Y. et al., “Leptin stimulates fatty-acidoxidation by activating AMP-activated protein kinase”, Nature, 415, 339,-2002)). In both ob/ob and db/db mice, 8 day AICAR administrationreduces blood glucose by 35% (Halseth A. E. et al., “Acute and chronictreatment of ob/ob and db/db mice with AICAR decreases blood glucoseconcentrations”, Biochem. Biophys. Res, Comm., 294, 798 (2002)). Inaddition to AICAR, it was found that the diabetes drug metformin canactivate AMPK in vivo at high concentrations (Zhou G. et al., “Role ofAMP-activated protein kinase in mechanism of metformin action”, J. Clin.Invest., 108, 1167, (2001), Musi N. et. al., “Metformin increasesAMP-activated protein kinase activity in skeletal muscle of subjectswith type 2 diabetes”, Diabetes, 51, 2074, (2002)), although it has tobe determined to what extent its antidiabetic action relies on thisactivation. As with leptin and adiponectin, the stimulatory effect ofmetformin is indirect via activation of an upstream kinase (Zhou G. etal., “Role of AMP-activated protein kinase in mechanism of metforminaction”, J. Clin. Invest., 108, 1167, (2001)). More recently, a smallmolecule AMPK activator have been described. This direct AMPK activator,named A-769662, a member of the Thienopyridone family in vivo induces adecrease in plasma glucose and triglycerides (Cool. B. et al.,“Identification and characterization of a small molecule AMPK activatorthat treats key components of type 2 diabetes and the metabolicsyndrome”, cell Metab., 3, 403-416, (2006)).

In addition to pharmacologic intervention, several transgenic mousemodels have been developed in the last years, and initial results arebecoming available. Expression of dominant negative AMPK in skeletalmuscle of transgenic mice has demonstrated the AICAR effect onstimulation of glucose transport is dependant of AMPK activation (Mu J.et al., “Role for AMP-activated protein kinase in contraction andhypoxia regulated glucose transport in skeletal muscle”, Molecular Cell,7, 1085, (2001)), and therefore likely not caused by non-specific DAPeffects. Similar studies in other tissues will help to further definethe consequences of AMPK activation. It is expected that pharmacologicactivation of AMPK will have benefits in the metabolic syndrome withimproved glucose and lipid metabolism and a reduction in body weight. Toqualify a patient as having metabolic syndrome, three out of the fivefollowing criteria must be met: elevated blood pressure above 130/85mmHg, fasting blood glucose above 110 mg/dl, abdominal obesity above 40″(men) or 35″ (women) waist circumference, and blood lipid changes asdefined by increase in triglycerides above 150 mg/dl or decrease HDLcholesterol below 40 mg/dl (men) or 50 mg/dl (women). Therefore, thecombined effects that may be achieved through activation of AMPK in apatient who qualifies as having metabolic syndrome would raise theinterest of this target.

Stimulation of AMPK has been shown stimulate expression of uncouplingprotein 3 (UCP3) skeletal muscle (Zhou m. et al., “UCP-3 expression inskeletal muscle: effects of exercise, hypoxia, and AMP-activated proteinkinase”, AM. J. Physiol. Endocrinol. Metab., 279, E622, (2000)) andmight therefore be a way to prevent damage from reactive oxygen species.Endothelial NO synthase (eNOS) has been shown to be activated throughAMPK mediated phosphorylation (Chen Z.-P. et at, “AMP-activated proteinkinase phosphorylation of endothelial NO synthase”, FEBS Letters, 443,286, (1999)), therefore AMPK activation can be used to improve localcirculatory systems.

AMPK has a role in regulating the mTOR pathway. mTOR is aserine/threonine kinase and is a key regulator of protein synthesis. Toinhibit cell growth and protect cells from apoptosis induced by glucosestarvation, AMPK phosphorylates TSC2 at Thr-1227 and Ser-1345 increasingthe activity of the TSC1 and TSC2 complex to inhibit m-TOR. In addition,AMPK inhibits mTOR action by phosphorylation on Thr-2446. Thus, AMPKindirectly and directly inhibits the activity of mTOR to limit proteinsynthesis. AMPK may also be a therapeutic target for many cancers thathave constitutive activation of the PI3K-Akt signalling pathway.Treatment of various cancer cell lines by AICAR attenuated the cellproliferation both in vitro and in vivo studies (Giri R; R.,“5-Aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside inhibits cancercell proliferation in vitro and in vivo via AMP-activated protein kinase(AMPK”, J. Biol. Chem. (2005)). Two reports link the treatment ofmetformin with a lower risk of cancer in diabetic patients (Evans J. M.“Metformin and reduced risk of cancer in diabetic patients”, BMJ, 330,1304-1305, (2005))

The activation of AMPK by AICAR has been shown to reduce expression ofthe lipogenic enzymes FAS and ACC, resulting in suppression ofproliferation in prostate cancer cells. Many cancer cells display amarkedly increased rate of de novo fatty acid synthesis correlated withhigh levels of FAS. Inhibition of FAS suppresses cancer cellproliferation and induces cell death. Thus, AMPK activation andinhibition of FAS activity is a clear target for pharmacological therapyof cancers.

In some publications it has been described that AICAR as an AMPKactivator exerts anti-inflammatory diseases. It has been observed thatAICAR attenuates the production of proinflammatory cytokines andmediators (S. Gin et al. J. Neuroscience 2004, 24:479-487), AICAR in ratmodel and in vitro attenuates EAE progression by limiting infiltrationof leucocytes across blood brain barrier (BBB) (N. Nath. Et al. J. ofImmunology 2005, 175:666-574; R. Prasad et al. J. Neurosci Res. 2006,84:614-625) and it has been suggested recently that AMPK activatingagents act as anti-inflammatory agents and can hold a therapeuticpotential in Krabbe disease/twitcher disease (an inherited neurologicaldisorder) (S. Giri et al. J. Neurochem. 2008, Mar. 19).

PRIOR ART

U.S. Pat. No. 5,602,144 discloses thienopyridone derivatives for thetreatment of cerebral ischemic or schizophrenia.

U.S. Pat. No. 7,119,205 discloses thienopyridones derivatives for thetreatment useful for the treatment of diabetes, obesity as AMPKactivators.

WO2007019914 discloses thienopyridone derivatives for the treatmentuseful for the treatment of diabetes, obesity as AMPK activators.

SUMMARY OF THE INVENTION

The invention relates to compounds of the formula (I)

in which:

-   R¹ denotes H, A, OA, OH, Hal, NO₂, COOA, COOH, CHO, COA, CONH₂,    CONHA, CONA₂, CN, SO₂A, SO₂NH₂, Ar or Het,-   R², R³ each, independently of one another, denote Ar or Het,-   Ar denotes phenyl, naphthyl, each of which is unsubstituted or    mono-, di-, tri-, tetra- or pentasubstituted by A, Hal, OA, OH, CHO,    COA, NH₂, NHA, NA₂, NO₂, COOA, COOH, CONH₂, COMA, CONA₂, SO₂A, CN,    C(═NH)NH₂, C(═NH)NHOH and/or Het,-   Het denotes a mono- or bicyclic unsaturated or aromatic heterocycle    having 1 to 4 N, O and/or S atoms, which may be mono-, di- or    trisubstituted by Hal, A, OA, OH, CHO, COA, COOH, COOA, CN, NO₂,    NH₂, NHA, NA₂, CONH₂, GONHA and/or CONA₂,-   A denotes unbranched or branched alkyl having 1-10 C atoms, in which    1-7 H atoms may be replaced by OH, F, Cl and/or Br, or denotes    cycloalkyl having 3-7 C atoms,-   Hal denotes F, Cl, Br or I,    and pharmaceutically usable salts and stereoisomers thereof,    including mixtures thereof in all ratios,    excluding compounds of the formula (I) where

—R¹=H; R²=phenyl; R³=3-methoxyphenyl

—R¹=H; R²=R³=phenyl

—R¹=H, R²=phenyl, R³=2-thiazoyl.

Some preferred compounds of formula (I) are the following:

-   3,5-diphenyl-4-hydroxy-2-methyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   methyl    3,5-diphenyl-4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-2-carboxylate,-   ethyl    3,5-diphenyl-4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-2-carboxylate,-   3,5-diphenyl-4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-2-carboxylic    acid,-   3,5-diphenyl-4-hydroxy-N-methyl-6-oxo-6,7-dihydro-thieno-[2,3-b]pyridine-2-carboxamide,-   3,5-diphenyl-4-hydroxy-2-hydroxymethyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-2,3,5-triphenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3,5-diphenyl-4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-carboxamide,-   3,5-diphenyl-4-hydroxy-2-methylsulfonyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-cyano-3,5-diphenyl-4-hydroxy-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-5-(2-hydroxyphenyl)-3-phenyl-2-methyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-5-(2-methoxyphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-5-(2-methoxyphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-5-(2-hydroxyphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-5-(2-benzyloxyphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-phenyl-5-(pyridin-4-yl)-2-methyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one-   4-hydroxy-3-phenyl-5-(pyridine-3-yl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-5-(4-methoxyphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-5-(4-methoxyphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one-   4-hydroxy-5-(4-hydroxyphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-5-(4-hydroxyphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-5-(4-cyanophenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-5-(4-dimethylaminophenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-5-(4-methoxyphenyl)-2-methyl-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-5-(4-hydroxyphenyl)-2-methyl-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-5-(4-(aminohydroxyiminomethyl)phenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-5-(4-methylsulfonylphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-(2-chloro-4-hydroxy-3-phenyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridin-5-yl)benzoic    acid,-   2-chloro-4-hydroxy-5-(4-trifluoromethylphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-(2-chloro-4-hydroxy-5-phenyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridin-3-yl)benzamide,-   N-methyl-4-(2-chloro-4-hydroxy-5-phenyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridin-3-yl)benzamide,-   2-chloro-4-hydroxy-5-(3-methoxyphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-5-(3-hydrophenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-5-(3-methoxyphenyl)-2-methyl-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-5-(3-methoxyphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-5-(3-cyanophenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-5-(3-(aminohydroxyiminomethyl)phenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-5-(3-methylsulfonylphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(2-chloro-4-hydroxy-5-phenyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridin-3-yl)benzoic    acid,-   4-hydroxy-5-(3-trifluoromethylphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-5-(3-trifluoromethylphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-5-(3-aminoiminomethylphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one    hydrochlorhyde-   N-methyl-3-(2-chloro-4-hydroxy-5-phenyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridin-3-yl)benzamide,-   3-(4-bromophenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one-   3-(4-chlorophenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(4-fluorophenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-3-(4-fluorophenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one-   3-(4-bromophenyl)-4-hydroxy-5-(pyridin-3-yl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(4-bromophenyl)-4-hydroxy-5-(pyridin-4-yl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(4-bromophenyl))-4-hydroxy-5-(pyridin-2-yl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(4-hydroxyphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(4-methoxyphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(4-methoxyphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(4-hydroxyphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(naphth-2-yl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(naphth-2-yl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(1-hydroxy-naphth-2-yl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(1-hydroxy-naphth-2-yl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(4-methylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(4-methylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one-   4-hydroxy-3-(4-trifluoromethylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(4-n-butylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(4-n-butylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(4-hydroxymethylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(4-tert-butylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(4-tert-butylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one-   4-hydroxy-3,5-di-(4-methoxyphenyl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3,5-di-(4-hydroxyphenyl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(4-methoxyphenyl)-5-(4-fluorophenyl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(4-hydroxyphenyl)-5-(4-fluorophenyl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(4-hydroxyphenyl)-5-(4-fluorophenyl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(4-fluorophenyl)-5-(4-methoxyphenyl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(4-fluorophenyl)-5-(4-hydroxyphenyl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(4-fluorophenyl)-5-(3-cyanophenyl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(2-chloro-4-hydroxy-3-(4-fluorophenyl)-6-oxo-6,7-dihydro-thieno[2,3-b]pyridin-5-yl)benzoic    acid,-   2-chloro-4-hydroxy-3-(4-methoxyphenyl)-5-(3-cyanophenyl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-(4-hydroxy-5-phenyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridin-3-yl)benzamide,-   4-hydroxy-3-(3-methoxyphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(3-methoxyphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(3-hydroxyphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(3-ethoxyphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(3-fluorophenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-3-(3-flurophenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(3-methylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(3-methylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(3-bromophenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(3-hydroxymethylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(3-hydroxymethylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(3-methylsulfonylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(2-chloro-4-hydroxy-5-phenyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridin-3-yl)benzoic    acid,-   4-hydroxy-3-(2-methoxyphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(2-methoxyphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(2-hydroxyphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(2-hydroxyphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(2-benzyloxyphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(2-fluorophenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-3-(2-fluorophenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(2-bromophenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(2-chlorophenyl)-4-hydroxy-6-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-3-(2-chlorophenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(2-methylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(2-methylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(2,4-dimethoxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(2,4-dihydroxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(2-fluoro-4-hydroxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-3-(2-fluoro-4-hydroxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(2-fluoro-4-methoxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-3-(2-fluoro-d-methoxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(2,4-difluorophenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-3-(2,4-difluorophenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(5-chloro-2-fluoro-4-hydroxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(2-benzyloxy-4-fluorophenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(2-benzyloxy-4-fluorophenyl)-2-chloro-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(2-hydroxy-4-fluorophenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(2-hydroxy-4-fluorophenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(3,5-dibenzyloxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(3,5-dihydroxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(3,5-dimethoxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(2-benzyloxy-5-fluorophenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(3-fluoro-4-methoxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-3-(3-fluoro-4-methoxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(3-fluoro-4-hydroxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-3-(3-fluoro-4-hydroxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(3-methoxy-4-bromophenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(3-hydroxy-4-bromophenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(5-fluoro-2-hydroxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-3-(5-fluoro-2-hydroxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(2-benzyloxy-5-fluorophenyl)-2-chloro-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(4-bromo-2-methoxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(4-bromo-2-hydroxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(2,6-difluorophenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-3-(2,6-diflurophenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(2-hydroxy-5-methoxyphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(2-benzyloxy-5-methoxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(2-hydroxy-4-methoxyphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(2-methoxy-4-methylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(2-methoxy-4-methylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(2-hydroxy-4-methylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(2-hydroxy-4-methylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(3-methoxy-4-methylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(3-methoxy-4-methylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(3-hydroxy-4-methylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(3-hydroxy-4-methylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(2-methoxy-4-methylphenyl)-5-(3-cyanophenyl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(2-hydroxy-4-methylphenyl)-5-(3-cyanophenyl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(2-hydroxy-4-methylphenyl)-5-(3-cyanophenyl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(2,6-dihydroxyphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(2-hydroxy-6-methoxyphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(1,4-benzodioxan-6-yl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(1,4-benzodioxan-6-yl)-2-chloro-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-3-(3,4-difluorophenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-(4-hydroxy-5-phenyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridin-3-yl)benzoic    acid,-   4-(2-chloro-4-hydroxy-5-phenyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridin-3-yl)benzoic    acid,-   3-(3-carboxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(furan-2-yl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-3-(furan-2-yl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(pyrazin-2-yl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-5-phenyl-3-(pyridin-3-yl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-5-phenyl-3-(pyridin-3-yl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-5-phenyl-3-(pyridin-4-yl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-5-phenyl-3-(pyridin-4-yl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-bromo-3,5-diphenyl-4-hydroxy-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-3,5-diphenyl-4-hydroxy-6,7-dihydro-thieno[2,3-b]pyridin-6-one.

A selection of these preferred compounds is

-   2-cyano-3,5-diphenyl-4-hydroxy-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-5-(3-methoxyphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(1-hydroxy-naphth-2-yl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(4-bromo-2-hydroxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(2-hydroxy-5-methoxyphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(2-hydroxy-4-methylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   4-hydroxy-3-(3-hydroxy-4-methylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,    4-hydroxy-3-(2-hydroxy-4-methylphenyl)-5-(3-cyanophenyl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(3-hydroxy-4-methylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(3-hydroxy-4-methylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(3-methoxy-4-methylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-3-(5-fluoro-2-hydroxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(4-fluorophenyl)-5-(3-cyanophenyl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(1-hydroxy-naphth-2-yl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   N-methyl-3-(2-chloro-4-hydroxy-5-phenyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridin-3-yl)benzamide,-   4-hydroxy-5-(2-methoxyphenyl)-2-methyl-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-5-(2-methylphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-5-(2-fluorophenyl)-4-hydroxy-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-phenyl-5-(pyridin-3-yl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-5-(6-methoxypyridin-3-yl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-phenyl-5-(thiophen-2-yl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-phenyl-5-(thiophen-3-yl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-5-(3-methyloxazol-5-yl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-5-(4-trifluoromethylphenyl)-4-hydroxy-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-5-(4-fluorophenyl)-4-hydroxy-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-5-(4-chlorophenyl)-4-hydroxy-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-5-(4-methylphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-5-(3-fluorophenyl)-4-hydroxy-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-5-(3-methylphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-5-(3,4-dimethoxyphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-3-(4-chlorophenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(napht-1-yl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(2-ethoxypyridin-5-yl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-3-(4-ethylphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-[4-(1-methylethyl)phenyl]-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-5-phenyl-3-(4-propylphenyl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(1-hydroxy-5-chloronapht-2-yl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-5-(4-fluorophenyl)-4-hydroxy-3-(1-hydroxynapht-2-yl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(1-hydroxynapht-2-yl))-5-(4-methylphenyl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-3-(4-fluoro-2-methoxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-]pyridin-6-one,-   3-(4-fluoro-2-hydroxyphenyl)-4-hydroxy-5-(4-methylphenyl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(5-fluoro-2-methoxyphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one-   2-chloro-4-hydroxy-3-(3,4-dimethoxyphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(4-fluoro-2-hydroxyphenyl)-4-hydroxy-5-(4-methoxyphenyl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-[2-Chloro-4-hydroxy-3-(2-hydroxy-4-methylphenyl)-6-oxo-6,7-dihydro-thieno[2,3-b]pyridin-5-yl]-benzoic    acid,-   2-chloro-3-(4,5-difluoro-2-hydroxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(2-hydroxy-4-methylphenyl)-5-(4-methylphenyl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(2-hydroxy-4-methylphenyl)-5-(pyridin-3-yl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(3,4-dimethylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-3-(3-fluoro-4-methyl-2-methoxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(3-fluoro-2-hydroxy-4-methylphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(3-fluoro-4-methyl-2-methoxyphenyl)-4-hydroxy-5-(4-methylphenyl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(3-fluoro-4-methyl-2-methoxyphenyl)-4-hydroxy-5-(4-fluorophenyl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(2-methoxy-3,4-dimethylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(2-hydroxy-3,4-dimethylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-3-(4-fluorophenyl)-5-(4-fluorophenyl)-4-hydroxy-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(3-fluoro-2-hydroxy-4-methylphenyl)-5-(4-fluorophenyl)-4-hydroxy-8,7-dihydro-thieno[2,3-b]pyridin-6-one,-   3-(3-fluoro-2-methoxy-4-methylphenyl)-5-(4-fluorophenyl)-4-hydroxy-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-3-(3-fluoro-2-hydroxy-4-methylphenyl)-5-(4-fluorophenyl)-4-hydroxy-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-4-hydroxy-3-(2-hydroxy-4,5-dimethylphenylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-3-(3,4-difluoro-2-hydroxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-3-(4-ethyl-2-hydroxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-3-(3-fluoro-2-hydroxy-4-methylphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-fluoro-3-(3-fluoro-2-hydroxy-4-methylphenyl)-5-(4-fluorophenyl)-4-hydroxy-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-3-(4-fluoro-2-hydroxyphenyl)-4-hydroxy-5-(4-methoxyphenyl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-3-(4-fluoro-2-hydroxyphenyl)-5-(4-fluorophenyl)-4-hydroxy-6,7-dihydro-thieno[2,3-b]pyridin-6-one,-   2-chloro-3-(4-fluoro-2-hydroxyphenyl)-4-hydroxy-5-(4-methylphenyl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one.

The invention relates to the compounds of the formula I and saltsthereof and to a process for the preparation of compounds of the formulaI according to claims 1-11 and pharmaceutically usable salts andstereoisomers thereof, characterised in that a compound of the formula(II)

-   -   wherein R¹, R², R³ have the meanings indicated in claim 1,    -   and ALK denotes C₁-C₆ alkyl        is cyclised under basic conditions,        and/or a base or acid of the formula I is converted into one of        its salts.

The invention also relates to the racemic forms, tautomeric forms,enantiomers, diastereoisomers, epimers and organic or mineral salts ofthe compounds of the general formula (I), as well as their crystallineforms, including their polymorphic forms and the polymorphic forms ofthe compounds of formula (I). The present invention is directed not onlyto racemic mixtures of these compounds, but also to individualstereoisomers and/or diastereoisomers thereof as well or as mixtures ofthese in all proportions. The invention also relates to thestereoisomers (including E, Z isomers) and the hydrates and solvates ofthese compounds. Solvates of the compounds are taken to mean adductionsof inert solvent molecules onto the compounds which form owing to theirmutual attractive force. Solvates are, for example, mono- or dihydratesor alcoholates.

Compounds of formula I also mean their pharmaceutically usablederivatives as well as their solvates. Pharmaceutically usablederivatives are taken to mean, for example, the salts of the compoundsaccording to the invention and also so-called prodrug compounds. Prodrugderivatives are taken to mean compounds of the formula I which have beenmodified, with, for example, alkyl or acyl groups, sugars oroligopeptides and which are rapidly cleaved in the organism to form theactive compounds according to the invention. These also includebiodegradable polymer derivatives of the compounds according to theinvention, as is described, for example, in Int. J. Pharm. 115, 61-67(1995). The term “prodrug” as used herein refers to any compound thatwhen administered to a biological system generates the “drug” substance(a biologically active compound) as a result of spontaneous chemicalreaction(s), enzyme catalyzed chemical reaction(s), and/or metabolicchemical reaction(s).

The expression “effective amount” means the amount of a medicament orpharmaceutical active ingredient which causes a biological or medicalresponse which is sought or aimed at, for example by a researcher orphysician, in a tissue, system, animal or human. In addition, theexpression “therapeutically effective amount” means an amount which,compared with a corresponding subject who has not received this amount,has the following consequence: improved treatment, healing, preventionor elimination of a disease, syndrome, condition, complaint, disorder orprevention of side effects or also the reduction in the progress of adisease, condition, disorder or side effects or also the reduction inthe progress of a disease, condition or disorder. The expression“therapeutically effective amount” also encompasses the amounts whichare effective for increasing normal physiological function.

The invention also relates to mixtures of the compounds of the formula Iaccording to the invention, for example mixtures of two diastereomers,for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.These are particularly preferably mixtures of stereoisomeric compounds.

For all radicals which occur more than once, their meanings areindependent of one another. Above and below, the radicals and parametersR¹, R², R³, have the meanings indicated for the formula I, unlessexpressly indicated otherwise.

A denotes alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4,5, 6, 7, 8, 9 or 10 C atoms. A preferably denotes methyl, furthermoreethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl,furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl,1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, further preferably, for example, trifluoromethyl.A very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 Catoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethylor 1,1,1-trifluoroethyl.

Moreover, A preferably denotes unbranched or branched alkyl having 1-10C atoms, in which 1-7H atoms may be replaced by OH, F and/or Cl.Cycloalkyl preferably denotes cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl.

R¹ preferably denotes H, A, Hal, COOA, COOH, CONH₂, CONHA, CONA₂, CN,SO₂A, SO₂NH₂ or phenyl.

R² preferably denotes phenyl, naphthyl, each of which is unsubstitutedor mono-, di-, tri-, tetra- or pentasubstituted by A, Hal, OA, OH, COOA,COOH, CONH₂, CONA, CONA₂ and/or SO₂A

or denotes Het.

R³ preferably denotes phenyl, naphthyl, each of which is unsubstitutedor mono-, di-, tri-, tetra- or pentasubstituted by A, Hal, OA, OH, NH₂,NHA, NA₂, COOA, COOH, CONH₂, CONA, CONA₂, SO₂A, CN, C(═NH)NH₂ and/orC(═NH)NHOH or denotes Het.

Ar denotes, for example, phenyl, o-, m- or p-tolyl, o-, m- orp-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, m-or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- orp-nitrophenyl, o-, m- or p-aminophenyl, o-, m- orp-(N-methylamino)phenyl, o-, m- or p-(N-methylaminocarbonyl)phenyl, o-,m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- orp-ethoxyphenyl, o-, m- or p-ethoxycarbonylphenyl, o-, m- orp-(N,N-dimethylamino)phenyl, o-, m- orp-(N,N-dimethylaminocarbonyl)phenyl, o-, m- or p-(N-ethylamino)phenyl,o-, m- or p-(N,N-diethylamino)phenyl, o-, m- or p-fluorophenyl, o-, m-or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- orp-(methylsulfonamido)phenyl, o-, m- or p-(methylsulfonyl)phenyl, o-, m-or p-cyanophenyl, o-, m- or p-ureidophenyl, m- or p-formylphenyl, o-, m-or p-acetylphenyl, o-, m- or p-aminosulfonylphenyl, o-, m- orp-carboxyphenyl, o-, m- or p-carboxymethylphenyl, o-, m- orp-carboxymethoxy-phenyl, further preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromo-phenyl,2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl,3-nitro-4-chlorophenyl, 3-amino-4-chloro-, 2-amino-3-chloro-,2-amino-4-chloro-, 2-amino-5-chloro- or 2-amino-6-chlorophenyl,2-nitro-4-N,N-dimethylamino- or 3-nitro-4-N,N-dimethylaminophenyl,2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or3,4,5-tri-chlorophenyl, 2,4,6-trimethoxyphenyl,2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl,4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl,3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl,3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.

Irrespective of further substitutions, Het denotes, for example, 2- or3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2,4- or5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably1,2,3-triazol-1-, -4- or 1,2,4-triazol-1-, -3- or 5-yl, 1- or5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-,3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or5-benzimidazolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 1-, 3-, 4-, 5-,6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6-or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6-or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-,4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl,3-, 4-, 5-, 6-, 7- or 8-innolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl,5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1,4-oxazinyl,further preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl,2,1,3-benzothiadiazol-4- or -5-yl or 2,1,3-benzoxadiazol-5-yl.

The heterocyclic radicals can also be partially or fully hydrogenated.

Het can thus also denote, for example, 2,3-dihydro-2-, -3-, -4- or-5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2- or-3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl,2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-,-4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or-4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl,tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or-4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-,2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or-4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3-or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -6-, -6-, -7- or-8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or8-3,4-dihydro-2H-benzo-1,4-oxazinyl, further preferably2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl,2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-(difluoromethylenedioxy)-phenyl, 2,3-dihydrobenzofuran-5- or 6-yl,2,3-(2-oxomethylenedioxy)phenyl or also3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably2,3-dihydro-benzofuranyl or 2,3-dihydro-2-oxofuranyl.

Het preferably denotes a mono- or bicyclic aromatic heterocycle having 1to 4 N, O and/or S atoms,

Most preferably Het denotes pyridyl, pyrimidinyl, furanyl, isoxazolyl,imidazolyl, pyrazolyl, oxazolyl, pyrrolyl, thiazolyl, isothiazolyl,thienyl, triazolyl, tetrazolyl, indolyl, benzimidazolyl or indazolyl.

Accordingly, the invention relates, in particular, to the compounds ofthe formula I in which at least one of the said radicals has one of thepreferred meanings indicated above. Some preferred groups of compoundsmay be expressed by the following sub-formulae Ia to Ig, which conformto the formula I and in which the radicals not designated in greaterdetail have the meaning indicated for the formula I, but in which

-   in Ia R¹ denotes H, A, Hal, COOA, COOH, CONH₂, CONHA, CONA₂, CN,    SO₂A, SO₂NH₂ or phenyl;-   in Ib R² denotes phenyl, naphthyl, each of which is unsubstituted or    mono-, di-, tri-, tetra- or pentasubstituted by A, Hal, OA, OH,    COOA, COOH, CONH₂, CONA, CONA₂ and/or SO₂A    -   or    -   denotes Het;-   in Ic R³ denotes phenyl, naphthyl, each of which is unsubstituted or    mono-, di-, tri-, tetra- or pentasubstituted by A, Hal, OA, OH, NH₂,    NHA, NA₂, COOA, COOH, CONH₂, CONA, CONA₂, SO₂A, CN, C(═NH)NH₂ and/or    C(═NH)NHOH    -   or    -   denotes Het;-   in Id Het denotes a mono- or bicyclic aromatic heterocycle having 1    to 4 N, O and/or S atoms;-   in Ie Het denotes pyridyl, pyrimidinyl, furanyl, isoxazolyl,    imidazolyl, pyrazolyl, oxazolyl, pyrrolyl, thiazolyl, isothiazolyl,    thienyl, triazolyl, etrazolyl, indolyl, benzimidazolyl or indazolyl;-   in If A denotes unbranched or branched alkyl having 1-10 C atoms, in    which 1-7H atoms may be replaced by OH, F, Cl and/or Br;-   in Ig R¹ denotes H, A, Hal, COOA, COOH, CONH₂, CONHA, CONA₂, CN,    SO₂A, SO₂NH₂ or phenyl,    -   R² denotes phenyl, naphthyl each of which is unsubstituted or        mono-, di-, tri-, tetra- or pentasubstituted by A, Hal, OA, OH,        COOA, COOH, CONH₂, CONA, CONA₂ and/or SO₂A        -   or        -   denotes Het,    -   R³ denotes phenyl, naphthyl, each of which is unsubstituted or        mono-, di-, tri-, tetra- or pentasubstituted by A, Hal, OA, OH,        NH₂, NHA, NA₂, COOA, COOH, CONH₂, CONA, CONA₂, SO₂A, CN,        C(═NH)NH₂ and/or C(═NH)NHOH        -   or        -   denotes Het,    -   Het denotes a mono- or bicyclic aromatic heterocycle having 1 to        4 N, O and/or S atoms,    -   A denotes unbranched or branched alkyl having 1-10 C atoms, in        which 1-7H atoms may be replaced by OH, F, Cl and/or Br,    -   Hal denotes F, Cl, Br or I;        and pharmaceutically usable salts and stereoisomers thereof,        including mixtures thereof in all ratios.        Preparation of Thienopyridone Derivatives of the Formula (I)

The compounds of the present invention may be prepared in a number ofmethods well known to those skilled in the art, including, but notlimited to those described below, or through modifications of thesemethods by applying standard techniques known to those skilled in theart of organic synthesis. All processes disclosed in association withthe present invention are contemplated to be practiced on any scale,including milligram, gram, multigram, kilogram, multikilogram orcommercial industrial scale.

It will be appreciated that the compounds of the present invention maycontain one or more asymmetrically substituted carbon atoms, and may beisolated in optically active or racemic forms. Thus, all chiral,diastereomeric, racemic forms and all geometric isomeric forms of astructure are intended, unless the specific stereochemistry or isomericform is specifically indicated. It is well known in the art how toprepare such optically active forms. For example, mixtures ofstereoisomers may be separated by standard techniques including, but notlimited to, resolution of racemic forms, normal, reverse-phase, andchiral chromatography, preferential salt formation, recrystallization,and the like, or by chiral synthesis either from active startingmaterials or by deliberate chiral synthesis of target centers.

In the reactions described hereinafter, it may be necessary to protectreactive functional groups, for example hydroxy, amino, imino, thio orcarboxy groups, where these are desired in the final product, to avoidtheir unwanted participation in the reactions. Conventional protectinggroups may be used in accordance with standard practice, for examplessee T. W. Greene and P. G. M. Wuts in Protective Groups in OrganicChemistry, John Wiley and Sons, 1991; J. F. W. McOmie in ProtectiveGroups in Organic Chemistry, Plenum Press, 1973.

Some reactions may be carried out in the presence of a base, There is noparticular restriction on the nature of the base to be used in thisreaction, and any base conventionally used in reactions of this type mayequally be used here, provided that it has no adverse effect on otherparts of the molecule. Examples of suitable bases include: sodiumhydroxide, potassium carbonate, potassium tertiobutylate, sodiumtertioamylate, triethylamine, potassium hexamethyldisilazide, alkalimetal hydrides, such as sodium hydride and potassium hydride;alkyllithium compounds, such as methyllithium and butyllithium; andalkali metal alkoxides, such as sodium methoxide and sodium ethoxide.

Usually, reactions are carried out in a suitable solvent. A variety ofsolvents may be used, provided that it has no adverse effect on thereaction or on the reagents involved. Examples of suitable solventsinclude: hydrocarbons, which may be aromatic, aliphatic orcycloaliphatic hydrocarbons, such as hexane, cyclohexane, benzene,toluene and xylene; amides, such as dimethylformamide; alcohols such asethanol and methanol and ethers, such as diethyl ether, dioxane andtetrahydrofuran.

The reactions can take place over a wide range of temperatures. Ingeneral, we find it convenient to carry out the reaction at atemperature of from 0° C. to 150° C. (more preferably from about roomtemperature to 100° C.). The time required for the reaction may alsovary widely, depending on many factors, notably the reaction temperatureand the nature of the reagents. However, provided that the reaction iseffected under the preferred conditions outlined above, a period of from3 hours to 20 hours will usually suffice.

The compound thus prepared may be recovered from the reaction mixture byconventional means. For example, the compounds may be recovered bydistilling off the solvent from the reaction mixture or, if necessary,after distilling off the solvent from the reaction mixture, pouring theresidue into water followed by extraction with a water-immiscibleorganic solvent and distilling off the solvent from the extract.Additionally, the product can, if desired, be further purified byvarious well-known techniques, such as recrystallization,reprecipitation or the various chromatography techniques, notably columnchromatography or preparative thin layer chromatography.

Compounds of formula (II) preferably are prepared by reaction of acompound of formula (III)

-   -   wherein R¹ and R² have the meanings as indicated in claim 1,        with a compound of formula (IV)        X—CO—CH₂—R³  (IV)    -   wherein R³ has the meanings as indicated in claim 1,    -   and X denotes a hydroxyl group or Cl, Br or I.

Most preferably X denotes Cl or Br.

The 2-aminothiophene starting compound (III) is a commercially available(chemos Gmbh, Fluorochem, Acros, Interchim) or easily prepared by aperson skilled in the Art by a Gewald reaction described in JournalHeterocycle Chemistry, vol. 36, page 333, 1999.

In the compounds of the formula IV, X is preferably Cl, Br, I or a freeor reactively modified OH group, such as, for example, an activatedester, an imidazolide or alkylsulfonyloxy having 1-6 carbon atoms(preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) orarylsulfonyloxy having 6-10 carbon atoms (preferably phenyl- orp-tolylsulfonyloxy).

Reaction Conditions:

a) Reacting compound of formula (III) with the compound of formula (IV)wherein X is a hydroxyl group in presence of a condensation agent inpresence of a base such as pyridine, triethylamine, disopropylethylaminein an aprotic solvent as tetrahydrofurane, acetonitrile at 20 to 80° C.preferably from 20 to 30° C.

The coupling agent is a carbodiimine derivative described in referenceinternet link (http://chemicalland21.com/lifescience/phar/HBTU.htm) withpreferably HBTU:2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate.

b) An alternative chemical pathway to prepare compound of formula (II)is reaction of compound (III) with compound (IV) wherein X is Cl, Br orI preferably Cl or Br in an aprotic solvent as tetrahydrofurane, dioxaneat a temperature comprised between 20 to 150 degree preferably between70 to 100° C.

Process of the synthesis of compound of formula (I)

Compound of the formula (I) is prepared from compound of formula (II) bya cyclisation reaction using a base as for, examplehexamethyldisilylazane, a potassium- or sodium salt, e.g. sodium- orpotassium tertioamylate, sodium ethylate with preferably use ofhexamethyldisylazide in an inert solvent, preferably in an aproticsolvent as for example tetrahydrofurane, dioxane, toluene at 20° C. to150° C. preferably 60 to 120° C. for 30 minutes to 24 hours preferentlyfrom 30 minutes to 1 hour.

Suitable inert solvents are, for example, hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitrites, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents.

Pharmaceutical Salts and Other Forms

The said compounds according to the invention can be used in their finalnon-salt form. On the other hand, the present invention also encompassesthe use of these compounds in the form of their pharmaceuticallyacceptable salts, which can be derived from various organic andinorganic acids and bases by procedures known in the art.Pharmaceutically acceptable salt forms of the compounds of the formula Iare for the most part prepared by conventional methods. If the compoundof the formula I contains a carboxyl group, one of its suitable saltscan be formed by reacting the compound with a suitable base to give thecorresponding base-addition salt. Such bases are, for example, alkalimetal hydroxides, including potassium hydroxide, sodium hydroxide andlithium hydroxide; alkaline earth metal hydroxides, such as bariumhydroxide and calcium hydroxide; alkali metal alkoxides, for examplepotassium ethoxide and sodium propoxide; and various organic bases, suchas piperidine, diethanolamine and N-methylglutamine. The aluminium saltsof the compounds of the formula I are likewise included. In the case ofcertain compounds of the formula I, acid-addition salts can be formed bytreating these compounds with pharmaceutically acceptable organic andinorganic acids, for example hydrogen halides, such as hydrogenchloride, hydrogen bromide or hydrogen iodide, other mineral acids andcorresponding salts thereof, such as sulfate, nitrate or phosphate andthe like, and alkyl- and monoaryl-sulfonates, such as ethanesulfonate,toluenesulfonate and benzenesulfonate, and other organic acids andcorresponding salts thereof, such as acetate, trifluoro-acetate,tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbateand the like. Accordingly, pharmaceutically acceptable add-additionsalts of the compounds of the formula I include the following: acetate,adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate(besylate), bisulfate, bisulfite, bromide, butyrate, camphorate,camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate,cyclopentanepropionate, digluconate, dihydrogen-phosphate,dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galacterate(from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate,glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate,hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate,lactobionate, malate, maleate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogen-phosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate, phthalate, but this does not represent a restriction.

Furthermore, the base salts of the compounds according to the inventioninclude aluminium, ammonium, calcium, copper, iron(III), iron(II),lithium, magnesium, manganese(III), manganese(II), potassium, sodium andzinc salts, but this is not intended to represent a restriction. Of theabove-mentioned salts, preference is given to ammonium; the alkali metalsalts sodium and potassium, and the alkaline earth metal salts calciumand magnesium. Salts of the compounds of the formula I which are derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary and tertiary amines, substituted amities, alsoincluding naturally occurring substituted amines, cyclic amines, andbasic ion ex-changer resins, for example arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine),dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropyl-amine and tris(hydroxymethyl)methylamine(tromethamine), but this is not intended to represent a restriction.

Compounds of the present invention which contain basicnitrogen-containing groups can be quaternised using agents such as(C₁-C₄)alkyl halides, for example methyl, ethyl, isopropyl andtert-butyl chloride, bromide and iodide; di(C₁-C₄)alkyl sulfates, forexample dimethyl, diethyl and diamyl sulfate; (C₁₀-C₁₈)alkyl halides,for example decyl, dodecyl, lauryl, myristyl and stearyl chloride,bromide and iodide; and aryl(C₁-C₄)alkyl halides, for example benzylchloride and phenethyl bromide. Both water- and oil-soluble compoundsaccording to the invention can be prepared using such salts.

The above-mentioned pharmaceutical salts which are preferred includeacetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate,mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodiumphosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate,tosylate and tromethamine, but this is not intended to represent arestriction.

The acid-addition salts of basic compounds of the formula I are preparedby bringing the free base form into contact with a sufficient amount ofthe desired acid, causing the formation of the salt in a conventionalmanner. The free base can be regenerated by bringing the salt form intocontact with a base and isolating the free base in a conventionalmanner. The free base forms differ in a certain respect from thecorresponding salt forms thereof with respect to certain physicalproperties, such as solubility in polar solvents; for the purposes ofthe invention, however, the salts otherwise correspond to the respectivefree base forms thereof.

As mentioned, the pharmaceutically acceptable base-addition salts of thecompounds of the formula I are formed with metals or amines, such asalkali metals and alkaline earth metals or organic amines. Preferredmetals are sodium, potassium, magnesium and calcium. Preferred organicamines are N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base-addition salts of acidic compounds according to the inventionare prepared by bringing the free acid form into contact with asufficient amount of the desired base, causing the formation of the saltin a conventional manner. The free acid can be regenerated by bringingthe salt form into contact with an acid and isolating the free acid in aconventional manner. The free acid forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts otherwise correspond tothe respective free acid forms thereof.

If a compound according to the invention contains more than one groupwhich is capable of forming pharmaceutically acceptable salts of thistype, the invention also encompasses multiple salts. Typical multiplesalt forms include, for example, bitartrate, diacetate, difumarate,dimeglumine, diphosphate, disodium and trihydrochloride, but this is notintended to represent a restriction.

With regard to that stated above, it can be seen that the expression“pharmaceutically acceptable salt” in the present connection is taken tomean an active ingredient which comprises a compound of the formula I inthe form of one of its salts, in particular if this salt form impartsimproved pharmacokinetic properties on the active ingredient comparedwith the free form of the active ingredient or any other salt form ofthe active ingredient used earlier. The pharmaceutically acceptable saltform of the active ingredient can also provide this active ingredientfor the first time with a desired pharmacokinetic property which it didnot have earlier and can even have a positive influence on thepharmacodynamics of this active ingredient with respect to itstherapeutic efficacy in the body.

Compounds of the formula I according to the invention may be chiralowing to their molecular structure and may accordingly occur in variousenantiomeric forms. They can therefore exist in racemic or in opticallyactive form.

Since the pharmaceutical activity of the racemates or stereoisomers ofthe compounds according to the invention may differ, it may be desirableto use the enantiomers. In these cases, the end product or even theintermediates can be separated into enantiomeric compounds by chemicalor physical measures known to the person skilled in the art or evenemployed as such in the synthesis.

In the case of racemic amines, diastereomers are formed from the mixtureby reaction with an optically active resolving agent. Examples ofsuitable resolving agents are optically active acids, such as the R andS forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid,mandelic acid, malic acid, lactic acid, suitably N-protected amino acids(for example N-benzoylproline or N-benzenesulfonylproline), or thevarious optically active camphorsulfonic acids. Also advantageous ischromatographic enantiomer resolution with the aid of an opticallyactive resolving agent (for example dinitrobenzoylphenylglycine,cellulose triacetate or other derivatives of carbohydrates or chirallyderivatised methacrylate polymers immobilised on silica gel). Suitableeluents for this purpose are aqueous or alcoholic solvent mixtures, suchas, for example, hexane/isopropanol/aceto-nitrile, for example in theratio 82:15:3.

For chiral resolution of the racemates following acids and amines can beused: As examples, the following chiral acids can be used(+)-D-di-O-benzoyltartaric acid, (−)-L-di-O-benzoyltartaric acid,(−)-L-di-O,O′-p-toluyl-L-tartaric acid,(+)-D-di-O,O′-p-toluoyl-L-tartaric acid, (R)-(+)-malic acid,(S)-(−)-malic acid, (+)-camphoric acid, (−)-camphoric acid, R-(−)1,1′-binaphtalen-2,2′-diyl hydrogenophosphonic, (+)-camphanic acid,(−)-camphanic acid, (S)-(+)-2-phenylpropionic acid,(R)-(+)-2-phenylpropionic acid, D-(−)-mandelic acid, L-(+)-mandelicacid, D-tartaric acid, L-tartaric acid, or any mixture of them.

As examples, the following chiral amines can be used: quinine, brucine,(S)-1-(benzyloxymethyl)propylamine (III), (−)-ephedrine,(4S,5R)-(+)-1,2,2,3,4-tetramethyl-5-phenyl-1,3-oxazolidine,(R)-1-phenyl-2-p-tolylethylamine, (S)-phenylglycinol,(−)-N-methylephedrine,(+)-(2S,3R)-4-dimethylamino-3-methyl-1,2-diphenyl-2-butanol,(S)-phenylglycinol, (S)-α-methylbenzylamine or any mixture of them.

The invention furthermore relates to the use of the compounds and/orphysiologically acceptable salts thereof for the preparation of amedicament (pharmaceutical composition), in particular by non-chemicalmethods. They can be converted into a suitable dosage form here togetherwith at least one solid, liquid and/or semi-liquid excipient or adjuvantand, if desired, in combination with one or more further activeingredients.

The invention furthermore relates to medicaments comprising at least onecompound according to the invention and/or pharmaceutically usablederivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios, and optionally excipients and/or adjuvants.

Pharmaceutical formulations can be administered in the form of dosageunits which comprise a predetermined amount of active ingredient perdosage unit. Such a unit can comprise, for example, 0.5 mg to 1 g,preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of acompound according to the invention, depending on the disease conditiontreated, the method of administration and the age, weight and conditionof the patient, or pharmaceutical formulations can be administered inthe form of dosage units which comprise a predetermined amount of activeingredient per dosage unit. Preferred dosage unit formulations are thosewhich comprise a daily dose or part-dose, as indicated above, or acorresponding fraction thereof of an active ingredient. Furthermore,pharmaceutical formulations of this type can be prepared using a processwhich is generally known in the pharmaceutical art.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) methods. Such formulationscan be prepared using all processes known in the pharmaceutical art by,for example, combining the active ingredient with the excipient(s) oradjuvant(s).

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

Thus, for example, in the case of oral administration in the form of atablet or capsule, the active-ingredient component can be combined withan oral, non-toxic and pharmaceutically acceptable inert excipient, suchas, for example, ethanol, glycerol, water and the like. Powders areprepared by comminuting the compound to a suitable fine size and mixingit with a pharmaceutical excipient comminuted in a similar manner, suchas, for example, an edible carbohydrate, such as, for example, starch ormannitol. A flavour, preservative, dispersant and dye may likewise bepresent.

Capsules are produced by preparing a powder mixture as described aboveand filling shaped gelatine shells therewith. Glidants and lubricants,such as, for example, highly disperse silicic acid, talc, magnesiumstearate, calcium stearate or polyethylene glycol in solid form, can beadded to the powder mixture before the filling operation. A disintegrantor solubiliser, such as, for example, agar-agar, calcium carbonate orsodium carbonate, may likewise be added in order to improve theavailability of the medicament after the capsule has been taken.

In addition, if desired or necessary, suitable binders, lubricants anddisintegrants as well as dyes can likewise be incorporated into themixture. Suitable binders include starch, gelatine, natural sugars, suchas, for example, glucose or beta-lactose, sweeteners made from maize,natural and synthetic rubber, such as, for example, acacia, tragacanthor sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes,and the like. The lubricants used in these dosage forms include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride and the like. The disintegrants include,without being restricted thereto, starch, methylcellulose, agar,bentonite, xanthan gum and the like. The tablets are formulated by, forexample, preparing a powder mixture, granulating or dry-pressing themixture, adding a lubricant and a disintegrant and pressing the entiremixture to give tablets. A powder mixture is prepared by mixing thecompound comminuted in a suitable manner with a diluent or a base, asdescribed above, and optionally with a binder, such as, for example,carboxymethylcellulose, an alginate, gelatine or polyvinylpyrrolidone, adissolution retardant, such as, for example, paraffin, an absorptionaccelerator, such as, for example, a quaternary salt, and/or anabsorbent, such as, for example, bentonite, kaolin or dicalciumphosphate. The powder mixture can be granulated by wetting it with abinder, such as, for example, syrup, starch paste, acacia mucilage orsolutions of cellulose or polymer materials and pressing it through asieve. As an alternative to granulation, the powder mixture can be runthrough a tableting machine, giving lumps of non-uniform shape which arebroken up to form granules. The granules can be lubricated by additionof stearic acid, a stearate salt, talc or mineral oil in order toprevent sticking to the tablet casting moulds. The lubricated mixture isthen pressed to give tablets. The compounds according to the inventioncan also be combined with a free-flowing inert excipient and thenpressed directly to give tablets without carrying out the granulation ordry-pressing steps. A transparent or opaque protective layer consistingof a shellac sealing layer, a layer of sugar or polymer material and agloss layer of wax may be present. Dyes can be added to these coatingsin order to be able to differentiate between different dosage units.

Oral liquids, such as, for example, solution, syrups and elixirs, can beprepared in the form of dosage units so that a given quantity comprisesa prespecified amount of the compounds. Syrups can be prepared bydissolving the compound in an aqueous solution with a suitable flavour,while elixirs are prepared using a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersion of the compound in anon-toxic vehicle. Solubilisers and emulsifiers, such as, for example,ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,preservatives, flavour additives, such as, for example, peppermint oilor natural sweeteners or saccharin, or other artificial sweeteners andthe like, can likewise be added.

The dosage unit formulations for oral administration can, if desired, been-capsulated in microcapsules. The formulation can also be prepared insuch a way that the release is extended or retarded, such as, forexample, by coating or embedding of particulate material in polymers,wax and the like.

The compounds according to the invention and salts, solvates andphysiologically functional derivatives thereof can also be administeredin the form of liposome delivery systems, such as, for example, smallunilamellar vesicles, large unilamellar vesicles and multilamellarvesicles. Liposomes can be formed from various phospholipids, such as,for example, cholesterol, stearylamine or phosphatidylcholines.

The compounds according to the invention and the salts, solvates andphysiologically functional derivatives thereof can also be deliveredusing monoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds can also be coupled to solublepolymers as targeted medicament carriers. Such polymers may encompasspolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidophenolor polyethylene oxide polylysine, substituted by palmitoyl radicals. Thecompounds may furthermore be coupled to a class of biodegradablepolymers which are suitable for achieving controlled release of amedicament, for example polylactic acid, poly-epsilon-caprolactone,polyhydroxybutyric acid, polyorthoesters, poly-acetals,polydihydroxypyrans, polycyanoacrylates and crosslinked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration canbe administered as independent plasters for extended, close contact withthe epidermis of the recipient. Thus, for example, the active ingredientcan be delivered from the plaster by iontophoresis, as described ingeneral terms in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compounds adapted for topical administration can beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissue, for example mouthand skin, the formulations are preferably applied as topical ointment orcream. In the case of formulation to give an ointment, the activeingredient can be employed either with a paraffinic or a water-misciblecream base. Alternatively, the active ingredient can be formulated togive a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical application to the eyeinclude eye drops, in which the active ingredient is dissolved orsuspended in a suitable carrier, in particular an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouthencompass lozenges, pastilles and mouthwashes.

Pharmaceutical formulations adapted for rectal administration can beadministered in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in whichthe carrier substance is a solid comprise a coarse powder having aparticle size, for example, in the range 20-500 microns, which isadministered in the manner in which snuff is taken, i.e. by rapidinhalation via the nasal passages from a container containing the powderheld close to the nose. Suitable formulations for administration asnasal spray or nose drops with a liquid as carrier substance encompassactive-ingredient solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalationencompass finely particulate dusts or mists, which can be generated byvarious types of pressurised dispensers with aerosols, nebulisers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration can beadministered as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions comprisingantioxidants, buffers, bacteriostatics and solutes, by means of whichthe formulation is rendered isotonic with the blood of the recipient tobe treated; and aqueous and non-aqueous sterile suspensions, which maycomprise suspension media and thickeners. The formulations can beadministered in single-dose or multidose containers, for example sealedampoules and vials, and stored in freeze-dried (lyophilised) state, sothat only the addition of the sterile carrier liquid, for example waterfor injection purposes, immediately before use is necessary.

Injection solutions and suspensions prepared in accordance with therecipe can be prepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavours.

A therapeutically effective amount of a compound of the presentinvention depends on a number of factors, including, for example, theage and weight of the human or animal, the precise disease conditionwhich requires treatment, and its severity, the nature of theformulation and the method of administration, and is ultimatelydetermined by the treating doctor or vet. However, an effective amountof a compound according to the invention is generally in the range from0.1 to 100 mg/kg of body weight of the recipient (mammal) per day andparticularly typically in the range from 1 to 10 mg/kg of body weightper day. Thus, the actual amount per day for an adult mammal weighing 70kg is usually between 70 and 700 mg, where this amount can beadministered as an individual dose per day or usually in a series ofpart-doses (such as, for example, two, three, four, five or six) perday, so that the total daily dose is the same. An effective amount of asalt or solvate or of a physiologically functional derivative thereofcan be determined as the fraction of the effective amount of thecompound according to the invention per se. It can be assumed thatsimilar doses are suitable for the treatment of other conditionsmentioned above.

EXAMPLES

Representative scheme of the cyclisation process is shown in the scheme1

The following examples illustrate the invention without, however,limiting it. The starting materials used are known products or productsprepared according to known procedures. The percentages are expressed ona weight basis, unless otherwise mentioned.

The compounds were characterised especially via the following analyticaltechniques.

The NMR spectra were acquired using a Bruker Avance DPX 300 MHz NMRspectrometer.

The masses were determined by HPLC coupled to an Agilent Series 1100mass detector. The melting points (m.p.) were measured on a StuartScientific block.

Example 14-hydroxy-3-phenyl-5-(pyridin-3-yl)-6,7-dihydro-thieno-[2,3-b]pyridin-6-one

Step 1: 3-pyridylacetic acid (0.842 g, 4.85 mmol) in acetonitrile (30mL) was cooled at 0° C. HBTU (2.169 g) and diisopropylethylamine (2.64g) was added. After 20 minutes of stirring, a solution of2-amino-3-ethoxycarbonyl-4-phenylthiophene (1 g, 4.04 mmol) inacetonitrile was added dropwise. After 15 h of stirring at roomtemperature, the solvent was removed under reduced pressure and theremaining was taken up into dichloromethane. This organic solution waswashed with sodium bicarbonate solution, water then dried over sodiumsulphate. Organic solvent was removed under reduced pressure and thecrude purified on silica (Heptane/ethyl acetate 4/6). A yellow oil (407mg) was recovered.

1HNMR (dmso-d6, 300 MHz): 11.45 (br. s, 1H), 8.64-8.59 (m, 2H),7.87-7.84 (m, 1H), 7.44-7.39 (m, 1H), 7.31-7.24 (m, 5H), 6.60 (s, 1H),4.03 (q, 2H), 3.88 (s, 2H), 0.89 (t, 3H)

Step 2: To the previous compound (197 mg) in tetrahydrofurane (2 mL) wasadded dropwise a solution of sodium hexamethyldisilylazide (3.58 mL, 4eq) in tetrahydrofurane. The solution was heated at 80° C. during 15hours then cooled to room temperature and acetic acid was added untilacid pH. All the solvents were removed under reduced pressure and wateradded. The precipitated white solid (120 mg) was filtered; MS: 321(M+1);

¹H NMR (DMSO-d₆, 300 MHz): 8.49 (bs, 1H), 8.48-8.40 (m, 1H), 7.77-7.70(m, 1H), 7.48-7.42 (m, 2H), 7.41-7.26 (m, 4H), 7.00 (m, 1H).

Example 24-hydroxy-5-(2-hydroxyphenyl)-3-phenyl-2-methyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one

Step 1: To a solution of propiophenone (30 mL, 0.226 mol) in ethanol(670 mL) was added dropwise ethyl cyanoacetate (24 After 20 minutes at60° C., morpholine (68.9 mL) was added and 5 minutes later sulphur (14.5g). Heating was carried on during 72 hours then the solvents removedunder reduced pressure. The crude was taken up with dichloromethane,filtered through a pad of silica and the solvent removed under reducedpressure, The crude was purified over silica (heptane/ethyl acetate 9/1)and a yellow solid was recovered (18.4 g);

¹H NMR (CDCl₃, 300 MHz): δ (ppm): 7.34-7.27 (m, 3H), 7.12-7.15 (m, 2H),3.91 (q, 2H), 2.02 (s, 3H), 0.78 (t, 3H)

Step 2: To the previous compound (800 mg) in dioxane (5 ml) was addeddropwise a solution of 2-methoxyphenylacetyl chloride (678 mg) indioxane (5 mL). The solution was heated to reflux during 15 hours thenthe solvent was removed under reduced pressure. The crude was taken upinto ethyl acetate and this solution was washed with a sodiumbicarbonate aqueous solution then water. The organic solution was driedover sodium sulfate and the solvent removed under reduced pressure. Ayellow oil was recovered (1.42 g);

¹H NMR (CDCl₃, 300 MHz): δ (ppm): 11.24 (br. s, 1H), 7.32-7.26 (m, 5H),7.12-7.08 (m, 2H), 6.99-6.91 (m, 2H), 3.89 (s, 3H), 3.88 (q, 2H), 3.82(s, 2H), 2.10 (s, 3H), 0.74 (t, 3H)

Step 3: The previous compound (1.4 g, 3.42 mmol) in tetrahydrofurane (20mL) was added dropwise to a solution of potassium hexamethyldisilylazide(27.4 mL of 0.5M in toluene). After 2 hours, the reaction was quenchedwith acetic acid and the solvents removed under reduced pressure, Thecrude solid was taken up into water and filtered. A pink solid wasrecovered (1.86 g); MS: 364.0 (M+1);

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 8.83 (br, s, 1H), 7.38-7.24 (m, 6H),7.04-7.02 (m, 1H), 6.96-6.87 (m, 2H), 3.65 (s, 3H), 2.19 (s, 3H).

Step 4: The previous solid (366 mg) in anhydrous dichloromethane (30 mL)was cooled to 0° C. Boron tribromide (4 ml, 1M solution indichloromethane) was added. After 3 hours of stirring at roomtemperature, the solution was taken up into a water/ice/triethylamine(few drops) mixture and stirred 1 hour. The organic phase was recovered,dried and concentrated under reduced pressure. The crude was purifiedover silica (dichloromethane/methanol 98/2). An off-white solid wasrecovered (60 mg); MS: 350.2 (M+1);

¹HNMR (DMSO-d₆, 300 MHz): 9.06 (bs, 1H), 7.38-7.25 (m, 5H), 7.12-6.99(m, 2H), 6.80-6.71 (m, 2H), 2.19 (s, 3H).

Example 32-chloro-4-hydroxy-3-(3-methoxyphenyl-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one

Step 1: Ethyl cyanoacetate (10.6 mL) was added dropwise to a solution of3′-methoxyacetophenone (13.7 mL, 0.1 mol) in ethanol (335 mL). After 20minutes at 60° C., morpholine (30.5 mL) was added and 5 minutes latersulphur (6.4 g). Heating was carried on during 72 hours then filteredthrough a pad of silica and the solvent removed under reduced pressure.The crude was purified over silica (heptane/ethyl actate 9/1). A yellowsolid was recovered (3.5 g);

¹H NMR (CDCl₃, 300 MHz): δ (ppm): 7.26-7.20 (m, 1H), 6.88-6.80 (m, 3H),6.07 (br. s, 1H), 4.04 (q, 2H), 3.81 (s, 3H), 0.95 (t, 3H).

Step 2: To a solution of the previous compound (1.5 g, 5.40 mmol),dioxane (9.3 mL) and pyridine (523 μL) was added dropwise phenylacetylchloride (858 μL). The reaction mixture was heated to 105° C. during 1hour then the solvent was evaporated. The crude was taken up intodichloromethane. The organic phase was washed twice by sodiumbicarbonate aqueous solution then dried over sodium sulfate. Afterremoval of the solvent by evaporation, the resulting oil was dissolvedin ethyl acetate and poured into heptane. The solid formed (1.44 g) wasfiltered and washed with heptane;

¹H NMR (CDCl₃, 300 MHz): δ (ppm): 11.22 (br. s, 1H), 7.44-7.28 (m, 5H),7.22 (dd, 1H), 6.88-6.76 (m, 3H), 6.59 (s, 1H), 4.01 (q, 2H), 3.84 (s,2H), 3.80 (s, 3H), 0.90 (t, 3H).

Step 3: A solution of the previous compound (1.44 g, 3.64 mmol),N-chlorosuccinimide (583 mg) and 1,2-dichloroethane (25 mL) was heatedat 40° C. for 1 hour. The reaction mixture was taken up intodichloromethane and washed twice with water then dried over sodiumsulfate and the solvent was evaporated. The crude was used without anyfurther purification;

¹H NMR (CDCl₃, 300 MHz): δ (ppm): 11.24 (br. s, 1H), 7.44-7.30 (m, 5H),7.24 (dd, 1H), 6.90-6.86 (m, 1H), 6.77-6.69 (m, 2H), 3.90 (q, 2H), 3.82(s, 2H), 3.78 (s, 3H), 0.78 (t, 3H).

Step 4: A solution of previous solid (3.64 mmol) in tetrahydrofurane (16mL) was added to potassium hexamethyldisilylazide (29 mL, 0.5M intoluene) and the reaction mixture was heated to 45° C. for 1 hour. Thereaction was quenched with acetic acid and the solvents removed underreduced pressure. The crude was purified over silica (pentane/ethylacetate (4/1) to get a pure solid (550 mg); MS: 384 (M+1);

¹H NMR (DMSO-d₆, 300 MHz): 11.60 (bs, 1H), 9.46 (bs, 1H), 7.41-720 (m,6H), 6.97-6.89 (m, 3H), 3.75 (s, 3H).

Example 42-cyano-3,5-diphenyl-4-hydroxy-6,7-dihydro-thieno[2,3-]pyridin-6-one

Step 1: A solution of benzonitrile (10 g, 97 mmol) and acetonitrile(10.2 mL, 195 mmol) was treated with potassium tert-butoxide (20 g)portionwise. The resulting thick suspension was stirred at roomtemperature overnight. Diethylether and sodium bicarbonate aqueoussolution were added. Aqueous solution was extracted with diethyletherand whole organic phases combinated. The organic solution was washedwith brine, dried over sodium sulfate and the solvents removed underreduced pressure. The resulting oil was taken up into ethyl acetate andpoured onto heptane. The yellow solid formed (8 g) was filtered andwashed with heptane;

¹H NMR (CDCl₃, 300 MHz): δ (ppm): 7.51-7.38 (m, 5H), 4.91 (bs, 21-1),4.24 (s, 1H).

Step 2: Ethyl cyanoacetate (3.4 mL) was added dropwise to a solution ofprevious compound (4.62 g, 32 mmol) in ethanol (95 mL). After 20 minutesat 60° C., piperidine (635 μL) was added and 5 minutes later sulphur(1.13 g). Heating was carried on during 72 hours then filtered through apad of silica and the solvent removed under reduced pressure. The crudewas purified over silica (pentane/ethyl actate 9/1). A yellow solid wasrecovered (1 g).

Step 3: To a solution of the previous compound (1 g, 3.67 mmol), dioxane(5 mL) and pyridine (200 μL) was added dropwise a solution ofphenylacetyl chloride (583 μL in 5 ml. of dioxane). The reaction mixturewas heated to 105° C. overnight then the solvent was evaporated. Thecrude was taken up by dichloromethane. The organic phase was washedtwice by sodium bicarbonate aqueous solution then dried over sodiumsulfate. A yellow solid (1.45 g) was recovered after removal of thesolvent by evaporation;

¹H NMR (CDCl₃, 300 MHz): δ (ppm): 11.46 (bs, 1H), 7.45-7.34 (m, 8H),7.26-7.23 (m, 2H), 3.96 (q, 2H), 3.89 (s, 2H), 0.82 (t, 3H).

Step 4: Potassium hexamethyldisilylazide (15 mL, 0.5M in toluene) wasadded dropwise to a solution of previous solid (600 mg, 1.54 mmol) intetrahydrofurane (60 mL) at 0° C. After 1 hour, the reaction wasquenched with methanol and the solvents removed under reduced pressure.The crude was taken up into a minimum methanol and hydrochloridesolution (4M) was added until acidic pH. A beige solid (260 mg) wasrecovered; MS; 345.1 (M+1);

¹H NMR (DMSO-d₆, 300 MHz): 10.00 (bs, 1H), 7.56-7.21 (m, 10H).

Example 52-chloro-3-(2,6-diflurophenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one

Step 1: Ethyl cyanoacetate (6.8 mL) was added dropwise to a solution of2′,6′-difluoroacetophenone (10 g, 64 mmol) in ethanol (250 mL). After 20minutes at 60° C., morpholine (19.6 mL) was added and 5 minutes latersulphur (4.1 g). Heating was carried on during 72 hours then filteredthrough a pad of silica and the solvent removed under reduced pressure.The crude was purified over silica (pentane/ethyl acetate 95/5). An oilycompound (13.5 g) containing ethylcyanoactate was recovered; MS: 284.0(M+1)

Step 2: To a solution of the previous compound (11.6 g, 20.4 mmol basedon a 50% purity), dioxane (30 mL) and pyridine (1.11 mL) was addeddropwise a solution of phenylacetyl chloride (3.24 mL in 25 ml. ofdioxane). After one hour, the solvent was evaporated under reducedpressure. The crude was taken up into dichloromethane. The organic phasewas washed twice by sodium bicarbonate aqueous solution then dried oversodium sulfate and the solvent was evaporated. The crude was purifiedover silica (pentane/ethylacetate 98/2) to provide the desired compound(1 g); MS: 402.1 (M+1);

¹H NMR (CDCl₃, 300 MHz): δ (ppm): 11.20 (hr. s, 1H), 7.42-7.23 (m, 6H),6.91-6.83 (m, 2H), 6.73 (s, 1H), 4.99 (q, 2H), 3.84 (s, 2H), 0.86 (t,3H).

Step 3: A solution of the previous compound (429 mg, 1 mmol),N-chlorosuccinimide (190 mg) and 1,2-dichloroethane (10 mL) was heatedat reflux overnight. The reaction mixture was taken up intodichloromethane and washed twice with water then dried over sodiumsulfate and the solvent was evaporated. The crude oil (410 mg) was usedwithout any further purification; MS: 436.0 (M+1);

¹H NMR (CDCl₃, 300 MHz): δ (ppm): 11.27 (br. s), 7.41-7.29 (m, 6H),5.95-6.89 (m, 2H), 3.96 (q, 2H), 3.84 (s, 2H), 0.83 (t, 3H).

Step 4: Potassium hexamethyldisilylazide (10 mL, 0.5M in toluene) wasadded dropwise to a solution of previous solid (410 mg, 0.94 mmol) intetrahydrofurane (50 mL) at 0° C. After 3 hours at room temperature, thereaction was quenched with methanol and the solvents removed underreduced pressure. The crude was taken up into a minimum methanol andhydrochloride solution (4M) was added until acidic pH. The precipitatedsolid was taken up into a minimum of ethyl acetate and poured ontoheptane. The precipitated solid (106 mg) was filtered and washed withheptane. A beige solid (260 mg) was recovered; MS: 389.7 (M+1);

¹H NMR (DMSO-d₆, 300 MHz): 9.76 (bs, 1H), 7.56-7.12 (m, 8H).

Example 64-hydroxy-3-(2-hydroxy-4-methylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one

Step 1: A solution of 2′-hydroxy-4′-methylacetophenone (10 g, 66.7mmol), potassium hydroxide (5 g), dimethylsulfate (7.6 mL) in acetone(175 mL) was stirred overnight. Triethylamine was added to destroyexcess of dimethylsulfate and the reaction mixture was filtered. Thesolvent was evaporated under reduced pressure. The solid obtained wasrecrystallised using pentane. White crystals (9 g) were recovered; MS:165.1 (M+1);

¹H NMR (CDCl₃, 300 MHz): δ (ppm): 7.68 (d, 1H), 6.80 (d, 1H), 6.77 (s,1H), 3.90 (s, 3H), 2.59 (s, 3H), 2.38 (s, 3H).

Step 2: Ethyl cyanoacetate (2.93 mL) was added dropwise to a solution ofprevious compound (4.5 g, 27.4 mmol) in ethanol (100 mL). After 20minutes at 60° C., morpholine (8.35 mL) was added and 5 minutes latersulphur (1.76 g). Heating was carried on during 72 hours then filteredthrough a pad of silica and the solvent removed under reduced pressure.The crude was purified over silica (pentane/ethyl actate 95/5). A yellowsolid (3.55 g) was recovered; MS: 292.1 (M+1);

¹H NMR (CDCl₃, 300 MHz): δ (ppm): 7.07 (d, 1H), 6.75 (d, 1H), 6.66 (s,1H), 6.06 (s, 1H), 4.00 (q, 2H), 3.72 (s, 3H), 2.38 (s, 3H), 0.91 (t,3H).

Step 3: To a solution of the previous compound (2 g, 6.87 mmol), dioxane(20 mL) and pyridine (671 μL) was added dropwise phenylacetyl chloride(995 μL). After 2 hours, the reaction mixture was taken up into ethylacetate and washed with water and brine. The organic solution was driedover sodium sulfate then the solvent was removed under reduced pressure.The crude oil was crystallised in a mixture of ethyl acetate/pentane. Ayellow solid (2.3 g) was recovered; MS: 410 (M+1);

¹H NMR (CDCl₃, 300 MHz): δ (ppm): 11.04 (bs, 1H), 7.45-7.25 (m, 5H),7.04 (d, 1H), 6.74 (d, 1H), 6.65 (s, 1H), 6.55 (s, 1H), 3.95 (q, 2H),3.82 (s, 2H), 3.67 (s, 3H), 2.37 (s, 3H), 0.86 (t, 3H).

Step 4: Potassium hexamethyldisilylazide (17.6 ml., 0.5M in toluene) wasadded dropwise to a solution of previous solid (900 mg, 2.2 mmol) intetrahydrofurane (40 mL) at 0° C. After 2 hours at room temperature, thereaction was quenched with acetic acid and the solvents removed underreduced pressure. The crude was taken up into water. The precipitatedsolid (650 mg) was filtered and washed with diethylether; MS: 364.1(M+1);

¹H NMR (DMSO-d₆, 300 MHz): 9.03 (bs, 1H), 7.40-7.15 (m, 5H), 7.08 (d,1H), 6.84 (s, 1H), 6.81 (s, 1H), 6.72 (d, 1H), 3.68 (s, 3H), 2.31 (s,3H).

Step 5: To a suspension of previous compound (250 mg, 0.69 mmol) indichloromethane was added boron tribromide (2.75 mL, 1M indichloromethane) at 0° C. After 30 minutes at 0° C. and 45 minutes atroom temperature, the reaction mixture was poured onto ice. The whitesolid precipitated (135 mg) was filtered and washed with diethylether;MS: 350.1 (M+1);

¹H NMR (DMSO-d₆, 300 MHz): 9.25 (bs, 1H), 7.34-7.22 (m, 5H), 7.03 (d,1H), 6.84 (s, 1H), 6.64 (s, 1H), 6.60 (d, 1H), 3.68 (s, 3H), 2.22 (s,3H).

The following compounds in Table I can be obtained analogously.

TABLE I R1 R2 R3 MS 1 ethoxycarbonyl phenyl phenyl 392.1 (M + 1) 2methoxy- phenyl phenyl 378.0 (M + 1) carbonyl 3 carboxy phenyl phenyl364.0 (M + 1) 4 (N-methyl)- phenyl phenyl 377.0 (M + 1) aminocarbonyl 5hydroxymethyl phenyl phenyl 350.0 (M + 1) 6 phenyl phenyl phenyl 396.1(M + 1) 7 aminocarbonyl phenyl phenyl 363.0 (M + 1) 8 methylsulfonylphenyl phenyl 398.1 (M + 1) 9 cyano phenyl phenyl 345.1 (M + 1) 10methyl phenyl phenyl 334.1 (M + 1) 11 methyl phenyl 2-hydroxyphenyl350.2 (M + 1) 12 methyl phenyl pyridin-4-yl 335.2 (M + 1) 13 methylphenyl 4-methoxyphenyl 364.2 (M + 1) 14 methyl phenyl 4-hydoxyphenyl350.2 (M + 1) 15 methyl phenyl 3-methoxyphenyl 364.2 (M + 1) 16 H phenylphenyl 320.0 (M + 1) 17 H phenyl 2-methoxyphenyl 350.0 (M + 1) 18 Hphenyl pyridin-3-yl 321.0 (M + 1) 19 H phenyl 4-methoxyphenyl 350.0(M + 1) 20 H phenyl 4-hydroxyphenyl 336.1 (M + 1) 21 H phenyl4-cyanophenyl 345.0 (M + 1) 22 H phenyl 4-dimethyl- 363.1 (M + 1)aminophenyl 23 H phenyl 3-methoxyphenyl 350.0 (M + 1) 24 H phenyl3-trifluoro- 388.1 (M + 1) methytphenyl 25 H 4-bromophenyl phenyl 400.0(M + 1) 26 H 4-chlorophenyl phenyl 354.0 (M + 1) 27 H 4-fluorophenylphenyl 338.0 (M + 1) 28 H 4-bromophenyl pyridin-3-yl 399.0 (M + 1) 29 H4-bromophenyl pyridin-4-yl 400.9 (M + 1) 30 H 4-bromophenyl Pyridin-2-yl400.9 (M + 1) 31 H 4-hydroxy- phenyl 336.1 (M + 1) phenyl 32 H4-methoxy- phenyl 350.1 (M + 1) phenyl 33 H naphth-2-yl phenyl 370.1(M + 1) 34 H 1-hydroxy- phenyl 386.1 (M + 1) naphth-2-yl 35 H4-methylphenyl phenyl 334.1 (M + 1) 36 H 4-trifluoro- phenyl 388.0(M + 1) methylphenyl 37 H 4-n-butylphenyl phenyl 376.1 (M + 1) 38 H4-hydroxy- phenyl 350.1 (M + 1) methylphenyl 39 H 4-tert-butyl- phenyl376.1 (M + 1) phenyl 40 H 4-methoxy- 4-methoxyphenyl 380.1 (M + 1)phenyl 41 H 4-hydroxy- 4-hydroxyphenyl 352.0 (M + 1) phenyl 42 H4-methoxy- 4-fluorophenyl 368.0 (M + 1) phenyl 43 H 4-hydroxy-4-fluorophenyl 354.1 (M + 1) phenyl 44 H 4-fluorophenyl 4-methoxyphenyl368.0 (M + 1) 45 H 4-fluorophenyl 4-hydroxyphenyl 354.1 (M+) 46 H4-amino- phenyl 363.0 (M + 1) carbonylphenyl 47 H 3-methoxy- phenyl349.9 (M + 1) phenyl 48 H 3-hydroxy- phenyl 336.0 (M + 1) phenyl 49 H3-fluorophenyl phenyl 338.1 (M + 1) 50 H 3-methylphenyl phenyl 334.0(M + 1) 51 H 3-bromophenyl phenyl 398.0 (M + 1) 52 H 3-hydroxy- phenyl350.1 (M + 1) methylphenyl 53 H 3-methyl- phenyl 398.0 (M + 1)sulfonylphenyl 54 H 2- phenyl 350.0 (M + 1) methoxyphenyl 55 H 2- phenyl336.2 (M + 1) hydroxyphenyl 56 H 2-fluorophenyl phenyl 338.1 (M + 1) 57H 2-bromophenyl phenyl 395.6 (M − 1) 58 H 2-chlorophenyl phenyl 354.0(M + 1) 59 H 2-methylphenyl phenyl 334.1 (M + 1) 60 H 2,4-dimethoxy-phenyl 380.1 (M + 1) phenyl 61 H 2,4-dihydroxy- phenyl 352.0 (M + 1)phenyl 62 H 2-fluoro-4- phenyl 352.0 (M − 1) hydroxyphenyl 63 H2-fluoro-4- phenyl 368.1 (M + 1) methoxyphenyl 64 H 2,4-difluoro- phenyl356.0 (M + 1) phenyl 65 H 2-benzyloxy-4- phenyl 444.1 (M + 1)fluorophenyl 66 H 4-fluoro-2- phenyl 352.0 (M − 1) hydroxyphenyl 67 H3,5- phenyl 532.0 (M + 1) dibenzyloxyphenyl 68 H 3,5-dihydroxy- phenyl352.1 (M + 1) phenyl 69 H 3,5-dimethoxy- phenyl 380.1 (M + 1) phenyl 70H 2-benzyloxy-5- phenyl 444.1 (M + 1) fluorophenyl 71 H 3-fluoro-4-phenyl 368.1 (M + 1) methoxyphenyl 72 H 3-fluoro-4- phenyl 354.1 (M + 1)hydroxyphenyl 73 H 4-bromo-3- phenyl 428.0 (M + 1) methoxyphenyl 74 H4-bromo-3- phenyl 413.9 (M + 1) hydroxyphenyl 75 H 5-fluoro-2- phenyl352.0 (M − 1) hydroxyphenyl 76 H 4-bromo-2- phenyl 427.9 (M + 1)methoxyphenyl 77 H 4-bromo-2- phenyl 413.9 (M + 1) hydroxyphenyl 78 H2,6-difluoro- phenyl 356.0 (M + 1) phenyl 79 H 2-hydroxy-5- phenyl 366.0(M + 1) methoxyphenyl 80 H 2-benzyloxy-5- phenyl 456.0 (M + 1)methoxyphenyl 81 H 2-hydroxy-4- phenyl 366.1 (M + 1) methoxyphenyl 82 H4-methyl-2- phenyl 364.1 (M + 1) methoxyphenyl 83 H 4-methyl-2- phenyl350.1 (M + 1) hydroxyphenyl 84 H 3-methoxy-4- phenyl 364.1 (M + 1)methylphenyl 85 H 3-hydroxy-4- phenyl 350.2 (M + 1) methylphenyl 86 H2-methoxy-4- 3-cyanophenyl 389.1 (M + 1) methylphenyl 87 H 2-hydroxy-4-3-cyanophenyl 375 (M + 1) methylphenyl 88 H 2,6-dihydroxy- phenyl 352(M + 1) phenyl 89 H 2-hydroxy-6- phenyl 366 (M + 1) methoxyphenyl 90 H4-carboxy- phenyl 364.1 (M + 1) phenyl 91 H 3-carboxy- phenyl 363.7(M + 1) phenyl 92 H Furan-2-yl phenyl 310.2 (M + 1) 93 H Pyrazin-2-ylphenyl 322.1 (M + 1) 94 H Pyridin-3-yl phenyl 321.1 (M + 1) 95 HPyridin-4-yl phenyl 321.0 (M + 1) 96 Cl Pyridin-4-yl phenyl 354.9(M + 1) 97 Cl Pyridin-3-yl phenyl 355.0 (M + 1) 98 Cl Furan-2-yl phenyl343.9 (M + 1) 99 Cl 4-carboxy- phenyl 398.0 (M + 1) phenyl 100 Cl3,4-difluoro- phenyl 390.0 (M + 1) phenyl 101 Cl 2-hydroxy-4-3-cyanophenyl 409.0 (M + 1) methylphenyl 102 Cl 3-hydroxy-4- phenyl384.0 (M + 1) methylphenyl 103 Cl 3-methoxy-4- phenyl 398.1 (M + 1)methylphenyl 104 Cl 2-hydroxy-4- phenyl 384.0 (M + 1) methylphenyl 105Cl 2-methoxy-4- phenyl 398.0 (M + 1) methylphenyl 106 Cl 2,6-difluorophenyl 389.7 (M + 1) phenyl 107 Cl 2-benzyloxy-5- phenyl 476 (M − 1)fluorophenyl 108 Cl 5-fluoro-2- phenyl 386 (M − 1) hydroxyphenyl 109 Cl3-fluoro-4- phenyl 388.0 (M + 1) hydroxyphenyl 110 Cl 3-fluoro-4- phenyl402.0 (M + 1) methoxyphenyl 111 Cl 4-fluoro-2- phenyl 386.0 (M − 1)hydroxyphenyl 112 Cl 2-benzyloxy-4- phenyl 478.1 (M + 1) fluorophenyl113 Cl 5-chloro-2- phenyl 421 (M + 1) fluoro-4- hydroxyphenyl 114 Cl2,4-difluoro- phenyl 390 (M + 1) phenyl 115 Cl 2-fluoro-4- phenyl 400 (M− 1) methoxyphenyl 116 Cl 2-fluoro-4- phenyl 388 (M + 1) hydroxyphenyl117 Cl 2-methylphenyl phenyl 368.0 (M + 1) 118 Cl 2-chlorophenyl phenyl387.9 (M + 1) 119 Cl 2-fluorophenyl phenyl 372 (M + 1) 120 Cl2-benzyloxy- phenyl 460.1 (M + 1) phenyl 121 Cl 2-hydroxy- phenyl 368.0(M − 1) phenyl 122 Cl 2-methoxy- phenyl 384.1 (M + 1) phenyl 123 Cl3-carboxy- phenyl 398.0 (M + 1) phenyl 124 Cl 3-hydroxy- phenyl 384.1(M + 1) methylphenyl 125 Cl 3-methylphenyl phenyl 368.0 (M + 1) 126 Cl3-fluorophenyl phenyl 372.0 (M + 1) 127 Cl 3-ethoxyphenyl phenyl 398.0(M + 1) 128 Cl 3-methoxy- phenyl 384.0 (M + 1) phenyl 129 Cl 4-methoxy-3-cyanophenyl 409.0 (M + 1) phenyl 130 Cl 4-fluorophenyl 3-carboxyphenyl416.0 (M + 1) 131 Cl 4-fluorophenyl 3-cyanophenyl 396.9 (M + 1) 132 Cl4-hydroxy- 4-fluorophenyl 388.1 (M + 1) phenyl 133 Cl 4-tert-butyl-phenyl 410.1 (M + 1) phenyl 134 Cl 4-n-butylphenyl phenyl 410 (M + 1)135 Cl 4-methyl phenyl 368.0 (M + 1) 136 Cl 1-hydroxy- phenyl 420.1(M + 1) naphth-2-yl 137 Cl Naphth-2-yl phenyl 404 (M + 1) 138 Cl4-hydroxy- phenyl 369.9 (M + 1) phenyl 139 Cl 4-methoxy- phenyl 384.0(M + 1) phenyl 140 Cl 4-fluorophenyl phenyl 372 (M + 1) 141 Cl phenylN-methyl-3-amino- 411 (M + 1) carbonylphenyl 142 Cl phenyl 3-aminoimino-396 (M + 1) methylphenyl 143 Cl phenyl 3-trifluoro- 422 (M + 1)methylphenyl 144 Cl phenyl 3-carboxyphenyl 379 (M + 1) 145 Cl phenyl3-methyl- 430 (M − 1) sulfonylphenyl 146 Cl phenyl 3-aminohydroxy- 412(M + 1) iminomethylphenyl 147 Cl phenyl 3-cyanophenyl 379 (M + 1) 148 Clphenyl 3-hydroxyphenyl 370.0 (M + 1) 149 Cl phenyl 3-methoxyphenyl 382.3(M − 1) 150 Cl phenyl N-methyl-4-amino- 409 (M − 1) carbonylphenyl 151Cl phenyl 4-amino- 395 (M − 1) carbonylphenyl 152 Cl phenyl 4-trifluoro-388 (M + 1) methylphenyl 153 Cl phenyl 4-carboxyphenyl 396 (M − 1) 154Cl phenyl 4-methylsulfonyl- 430 (M − 1) phenyl 155 Cl phenyl4-aminohydroxy- 412 (M + 1) iminomethylphenyl 156 Cl phenyl4-hydroxyphenyl 370.2 (M + 1) 157 Cl phenyl 4-methoxyphenyl 384.0(M + 1) 158 Cl phenyl 2-benzyloxyphenyl 460.1 (M + 1) 159 Cl phenyl2-hydroxyphenyl 370.0 (M + 1) 160 Cl phenyl 2-methoxyphenyl 383.9(M + 1) 161 Br phenyl phenyl 397.5 (M + 1) 162 Cl phenyl phenyl 353.8(M + 1) 163 Methyl phenyl 2-methoxyphenyl 364.0 (M + 1) 164 chlorophenyl 2-methylphenyl 367.1 (M + 1) 165 chloro phenyl 2-fluorophenyl 372(M + 1) 166 chloro phenyl Pyridin-3-yl 355 (M + 1) 167 chloro phenyl6-methoxypyridin-3- 384.9 (M + 1) yl 168 chloro phenyl Thiophen-2-yl359.8 (M + 1) 169 chloro phenyl Thiophen-3-yl 359.8 (M + 1) 170 chlorophenyl 3-methyloxazol-5-yl 358.9 (M + 1) 171 chloro phenyl 4- 422(M + 1) trifluoromethylphenyl 172 chloro phenyl 4-fluorophenyl 372(M + 1) 173 chloro phenyl 4-chlorophenyl 388 (M + 1) 174 chloro phenyl4-methylphenyl 368 (M + 1) 175 chloro phenyl 3-fluorophenyl 372 (M + 1)176 chloro phenyl 3-methylphenyl 368 (M + 1) 177 chloro phenyl 3,4- 414(M + 1) dimethoxyphenyl 178 chloro 4-chlorophenyl phenyl 388 (M + 1) 179chloro Naphth-yl phenyl 403.6 (M + 1) 180 H 2-ethoxypyridin- phenyl 365(M + 1) 5-yl 181 chloro 4-ethylphenyl phenyl 382 (M + 1) 182 chloro 4-phenyl 396 (M + 1) isopropylphenyl 183 chloro 4-propylphenyl phenyl396.3 (M + 1) 184 chloro 5-chloro-1- Phenyl 454 (M + 1) hydroxynaphth-2-yl 185 chloro 1- 4-fluorophenyl 438 (M + 1) hydroxynaphth- 2-yl 186chloro 1- 4-methylphenyl 434 (M + 1) hydroxynaphth- 2-yl 187 chloro4-fluoro-2- phenyl 402 (M + 1) methoxyphenyl 188 H 4-fluoro-2-4-methylphenyl 368 (M + 1) hydroxyphenyl 189 chloro 5-fluoro-2- phenyl402 (M + 1) methoxyphenyl 190 chloro 3,4- phenyl 414.1 (M + 1)dimethoxyphenyl 191 H 4-fluoro-2- 4-methoxyphenyl 384.0 (M + 1)hydroxyphenyl 192 chloro 2-hydroxy-4- 3-carboxyphenyl 428.3 (M + 1)methylphenyl 193 chloro 4,5-difluoro-2- phenyl 406 (M + 1) hydroxy 194chloro 2-hydroxy-4- 4-methylphenyl 398 (M + 1) methylphenyl 195 chloro2-hydroxy-4- Pyridin-3-yl 385.1 (M + 1) methylphenyl 196 chloro 3,4-phenyl 382 (M + 1) dimethylphenyl 197 chloro 3-fluoro-2- phenyl 382(M + 1) methoxy-4- methylphenyl 198 H 3-fluoro-2- phenyl 366 (M − 1)hydroxy-4- methylphenyl 199 H 3-fluoro-2- 4-methylphenyl 394 (M − 1)hydroxy-4- methylphenyl 200 H 3-fluoro-2- 4-fluorophenyl 398 (M − 1)hydroxy-4- methylphenyl 201 chloro 2-methoxy-3,4- phenyl 410 (M − 1)dimethylphenyl 202 chloro 2-hydroxy-3,4- phenyl 398 (M + 1)dimethylphenyl 203 chloro 4-fluorophenyl 4-fluorophenyl 390 (M + 1) 204H 3-fluoro-2- 4-fluorophenyl 386 (M + 1) hydroxy-4- methylphenyl 205 H3-fluoro-2- 4-fluorophenyl 434 (M + 1) methoxy-4- methylphenyl 206chloro 3-fluoro-2- 4-fluorophenyl 420 (M + 1) hydroxy-4- methylphenyl207 chloro 2-hydroxy-4,5- phenyl 398 (M + 1 dimethylphenyl 208 chloro3,4-difluoro-2- phenyl 406 (M + 1) hydroxyphenyl 209 chloro 4-ethyl-2-phenyl 398 (M + 1) hydroxyphenyl 210 chloro 3-fluoro-2- phenyl 402(M + 1) hydroxy-4- methylphenyl 211 fluoro 3-fluoro-2- 4-fluorophenyl402 (M − 1) hydroxy-4- methylphenyl 212 chloro 4-fluoro-2-4-methoxyphenyl 418 (M + 1) hydroxyphenyl 213 chloro 4-fluoro-2-4-fluorophenyl 406 (M + 1) hydroxyphenyl 214 chloro 4-fluoro-2-4-methylphenyl 402 (M + 1) hydroxyphenylBiological Assays

Enzymatic Activity

The following biological test allows the determination of the efficacyof such compounds of formula (I) onto AMPK protein (recombinant α1β1γ2).

Human recombinant AMPK enzyme was expressed in E. Coli and wasreactivated in vitro by LKB1 prior to enzyme activity determination.

AMPK enzyme activities were assayed by using A Delfia technology. AMPKenzyme activities were carried out in microtiter plates (50 mM Hepesbuffer, pH 7.4 with 125 μM ATP respectively) in the presence of asynthetic peptide substrate (AMARAASAAALARRR, the “AMARA” peptide) andactivators in serial dilutions. Reactions were initiated by the additionof AMPK (50-100 ng). Following mixing, the plates were incubated for 30min at room temperature. Enzyme activity was assayed by using ananti-phosphoserine antibody to measure the quantity of phosphateincorporated into the AMARAA.

N°: Number of the molecule

Activity: Ratio between the % of control (basal activity) of compound offormula (I) at 30 μM and the % of control (basal activity) of AMP(natural substrate) at 30 μM.

Compounds of formula (I) in the table II are considered as directactivator of AMPK if the ratio is 90% or higher.

TABLE II no. activity no. activity no. activity no. activity 3 102 20 9932 147 42 110 9 410 22 121 33 201 44 98 10 96 23 202 34 625 45 114 13126 25 119 35 126 47 117 14 116 26 128 36 121 48 109 15 181 27 114 38119 49 131 16 107 28 109 40 109 50 103 19 96 29 103 41 92 52 176 55 14663 115 73 94 81 223 56 107 64 109 74 112 83 403 58 103 66 144 75 135 84158 60 100 68 96 77 257 85 406 61 146 71 131 78 160 87 287 62 101 72 15079 593 100 103 104 236 111 136 121 143 129 102 105 206 113 95 124 195130 117 106 115 114 115 125 101 131 331 108 305 115 118 126 98 132 108109 200 116 120 127 122 134 93 110 121 119 101 128 181 135 113 136 488142 126 149 120 155 95 137 129 143 99 150 130 156 95 138 114 144 116 151134 157 147 139 114 145 90 152 99 158 110 140 123 146 103 153 111 159164 141 403 148 121 154 131 161 113 162 107 164 354 176 245 189 175 204189 165 238 177 234 190 256 205 148 166 225 178 138 191 187 206 184 167592 179 284 192 193 207 213 168 174 181 559 193 139 208 131 169 196 182165 194 183 209 297 170 423 183 146 195 156 210 181 171 147 184 167 196165 211 149 172 153 185 284 198 363 212 183 173 160 186 192 201 122 213349 174 245 187 124 202 305 214 207 175 252 188 183 203 251Glucose Uptake in Muscle

Skeletal muscle is the major site of insulin-stimulated glucose disposaland insulin resistance in this target tissue has long been viewed as acontribution factor in the pathogenesis of type 2 diabetes (T2D).Therefore alternative pathways that stimulate skeletal muscle glucoseuptake independently of insulin signaling could potentially improveglycemic control in T2D subjects. Although exercise stimulates glucoseuptake in skeletal muscle independently of the insulin pathway, theunderlying molecular mechanisms remains largely elusive. The findingthat the glucose transport can be increased in isolated skeletal musclein response to contraction in vitro suggests that the signaling pathwayselicited by internal cellular energy deficiency are partly accountablefor contraction-induced glucose uptake. AMPK is considered as anattractive candidate for contraction-induced skeletal muscle glucoseuptake because it is activated in parallel with elevation in AMP and areduction in creatine phosphate energy stores (Hubter C. A., Am. J.Physiol. Endocrinol. Metab. 272:E262-E266; 1997). Furthermore,AICAR-induced activation of AMPK increases glucose uptake (Merrill G. F.and al., Am. J. Physiol. Endocrinol. Metab. 273:E1107-E1112; 1997).

Glucose Uptake in H-2 Kb Cells (In Vitro Cellular Test)

The following cellular test allows the determination of the effect ofAMPK activators such as compounds of formula (I) onto glucose uptake ina muscle cellular model.

H-1-2 Kb cells derived from heterozygous H-2 Kb tsA58 transgenic mousewere grown in 24-well in plates coated with matrigel and were culturedat 33° C. for 4 days under permissive conditions, as describedpreviously by Fryer et al. (Diabetes 49 (12): 1978, 2000).

For differentiation in muscle, cells were switched to non-permissiveculture conditions (37° C. in the absence of interferon-γ). After 3days, cells were incubated for 4 hours in DMEM 1 g/l glucose culturemedium containing different concentrations of the tested molecules. Thenglucose uptake was measured by incubating the cells for 10 min withradiolabelled 2-deoxy-D-[1,2 ³H] glucose. Glucose uptake was terminatedby rapidly washing the plates 2 times with ice-cold NaCl 0.9%. The cellswere then solubilized in 0.1N NaOH for 30 min. Radioactivity wasdetermined by liquid scintillation counting.

N°: Number of the molecule

Activity (table III): Concentration of compound (I) for a glucose uptakeequal or higher to glucose uptake induced by insulin (170 nM)

⁺⁺ or **concentration of compound (I) ≦10 micro Molar

⁺ or *concentration of compound (I) >10 micro Molar

TABLE III N° activity N° activity N° activity N° activity N° activity9 * 27 * 102 ** 126 * 143 * 10 * 33 * 103 * 127 * 148 ** 13 * 34 * 104 *128 * 149 ** 14 * 35 ** 108 * 129 ** 156 ** 15 * 36 * 109 ** 131 * 157** 19 * 47 * 111 * 136 ** 161 ** 20 * 63 * 115 ** 137 * 162 ** 22 **83 * 119 * 138 ** 23 * 100 ** 121 * 139 ** 26 * 101 * 125 ** 140 **164 + 176 ++ 189 + 204 + 165 + 177 ++ 190 + 205 + 166 + 178 ++ 191 +206 + 167 ++ 179 ++ 192 ++ 207 + 168 ++ 181 ++ 193 + 208 + 169 ++ 182 +194 ++ 209 ++ 170 ++ 183 + 195 + 210 ++ 171 + 184 ++ 196 ++ 211 + 172 +185 ++ 198 + 212 + 173 ++ 186 ++ 201 + 213 + 174 + 187 + 202 ++ 175 +188 +

Compounds of the invention are able to increase glucose uptake in amuscular cell line named H-2 Kb independently of insulin.

These data resulting of an enzymatic test followed by a cellular testshows that thienopyridone derivatives as defined in formula (I) aredirect AMPK activators and these compounds are able to increase glucoseuptake preferably in muscular cells.

The invention claimed is:
 1. A compound of the formula (I)

in which: R¹ denotes Hal, R², R³ each, independently of one another,denote Ar or Het, Ar denotes phenyl, naphthyl, each of which isunsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by A, Hal,OA, OH, CHO, COA, NH₂, NHA, NA₂, NO₂, COOA, COOH, CONH₂, CONHA, CONA₂,SO₂A, CN, C(═NH)NH₂, C(═NH)NHOH and/or Het, Het denotes a mono- orbicyclic aromatic heterocycle having 1 to 4 N, O and/or S atoms, whichmay be mono-, di- or trisubstituted by Hal, A, OA, OH, CHO, COA, COOH,COOA, CN, NO₂, NH₂, NHA, NA₂, CONH₂, CONHA and/or CONA₂, A denotesunbranched or branched alkyl having 1-10 C atoms, in which 1-7 H atomsmay be replaced by OH, F, Cl and/or Br, or denotes cycloalkyl having 3-7C atoms, Hal denotes F, Cl, Br or I, or a pharmaceutically usable salt,solvate or stereoisomer thereof, including a mixture of stereoisomers inany ratio.
 2. A compound according to claim 1 in which R² denotesphenyl, naphthyl each of which is unsubstituted or mono-, di-, tri-,tetra- or pentasubstituted by A, Hal, OA, OH, COOA, COOH, CONH₂, CONHA,CONA₂ and/or SO₂A or denotes Het, or a pharmaceutically usable salt orstereoisomer thereof, including a mixture of stereoisomers in any ratio.3. A compound according to claim 1 in which R³ denotes phenyl, naphthyl,each of which is unsubstituted or mono-, di-, tri-, tetra- orpentasubstituted by A, Hal, OA, OH, NH₂, NHA, NA₂, COOA, COOH, CONH₂,CONHA, CONA₂, SO₂A, CN, C(═NH)NH₂ and/or C(═NH)NHOH or denotes Het, or apharmaceutically usable salt or stereoisomer thereof, including amixture of stereoisomers in any ratio.
 4. A compound according to claim1 in which R² denotes Het and/or R³ denotes Het, or a pharmaceuticallyusable salt or stereoisomer thereof, including a mixture ofstereoisomers in any ratio.
 5. A compound according to claim 1 in whichHet denotes pyridyl, pyrimidinyl, furanyl, isoxazolyl, imidazolyl,pyrazolyl, oxazolyl, pyrrolyl, thiazolyl, isothiazolyl, thienyl,triazolyl, tetrazolyl, indolyl, benzimidazolyl or indazolyl, or apharmaceutically usable salt or stereoisomer thereof, including amixture of stereoisomers in any ratio.
 6. A compound according to claim1 in which A denotes unbranched or branched alkyl having 1-10 C atoms,in which 1-7 H atoms may be replaced by OH, F, Cl and/or Br, or apharmaceutically usable salt or stereoisomer thereof, including amixture of stereoisomers in any ratio.
 7. A compound according to claim1 in which R¹ denotes Hal, R² denotes phenyl, naphthyl, each of which isunsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by A, Hal,OA, OH, COOA, COOH, CONH₂, CONHA, CONA₂ and/or SO₂A or denotes Het, R³denotes phenyl, naphthyl, each of which is unsubstituted or mono-, di-,tri-, tetra- or pentasubstituted by A, Hal, OA, OH, NH₂, NHA, NA₂, COOA,COOH, CONH₂, CONA, CONA₂, SO₂A, CN, C(═NH)NH₂ and/or C(═NH)NHOH ordenotes Het, Het denotes a mono- or bicyclic aromatic heterocycle having1 to 4 N, O and/or S atoms, A denotes unbranched or branched alkylhaving 1-10 C atoms, in which 1-7 H atoms may be replaced by OH, F, Cland/or Br, Hal denotes F, Cl, Br or I, or a pharmaceutically usable saltor stereoisomer thereof, including a mixture of stereoisomers in anyratio.
 8. A compound according to claim 1, selected from the followingcompounds:2-chloro-4-hydroxy-5-(2-methoxyphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-5-(2-hydroxyphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-5-(2-benzyloxyphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-5-(4-methoxyphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-5-(4-hydroxyphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-5-(4-(aminohydroxyiminomethyl)phenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-5-(4-methylsulfonylphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,4-(2-chloro-4-hydroxy-3-phenyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridin-5-yl)benzoicacid,2-chloro-4-hydroxy-5-(4-trifluoromethylphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,4-(2-chloro-4-hydroxy-5-phenyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridin-3-yl)benzamide,N-methyl-4-(2-chloro-4-hydroxy-5-phenyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridin-3-yl)benzamide,2-chloro-4-hydroxy-5-(3-methoxyphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-5-(3-hydroxyphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one2-chloro-4-hydroxy-5-(3-cyanophenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-5-(3-(aminohydroxyiminomethyl)phenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-5-(3-methylsulfonylphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,3-(2-chloro-4-hydroxy-5-phenyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridin-3-yl)benzoicacid,2-chloro-4-hydroxy-5-(3-trifluoromethylphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-5-(3-aminoiminomethylphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-onehydrochloride,N-methyl-3-(2-chloro-4-hydroxy-5-phenyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridin-3-yl)benzamide,2-chloro-3-(4-fluorophenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(4-methoxyphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(4-hydroxyphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(naphth-2-yl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(1-hydroxy-naphth-2-yl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(4-methylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(4-n-butylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(4-tert-butylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(4-hydroxyphenyl)-5-(4-fluorophenyl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(4-fluorophenyl)-5-(3-cyanophenyl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,3-(2-chloro-4-hydroxy-3-(4-fluorophenyl)-6-oxo-6,7-dihydro-thieno[2,3-b]pyridin-5-yl)benzoicacid,2-chloro-4-hydroxy-3-(4-methoxyphenyl)-5-(3-cyanophenyl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(3-methoxyphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(3-ethoxyphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-3-(3-fluorophenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(3-methylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(3-hydroxymethylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,3-(2-chloro-4-hydroxy-5-phenyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridin-3-yl)benzoicacid,2-chloro-4-hydroxy-3-(2-methoxyphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(2-hydroxyphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(2-benzyloxyphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-3-(2-fluorophenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-3-(2-chlorophenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(2-methylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-3-(2-fluoro-4-hydroxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-3-(2-fluoro-4-methoxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-3-(2,4-difluorophenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,3-(2-benzyloxy-4-fluorophenyl)-2-chloro-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(2-hydroxy-4-fluorophenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-3-(3-fluoro-4-methoxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-3-(3-fluoro-4-hydroxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-3-(5-fluoro-2-hydroxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,3-(2-benzyloxy-5-fluorophenyl)-2-chloro-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-3-(2,6-difluorophenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(2-methoxy-4-methylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(2-hydroxy-4-methylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(3-methoxy-4-methylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(3-hydroxy-4-methylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(2-hydroxy-4-methylphenyl)-5-(3-cyanophenyl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-3-(3,4-difluorophenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,4-(2-chloro-4-hydroxy-5-phenyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridin-3-yl)benzoicacid,2-chloro-3-(furan-2-yl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-5-phenyl-3-(pyridin-3-yl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-5-phenyl-3-(pyridin-4-yl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-bromo-3,5-diphenyl-4-hydroxy-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-3,5-diphenyl-4-hydroxy-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-5-(2-methylphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-5-(2-fluorophenyl)-4-hydroxy-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-phenyl-5-(pyridin-3-yl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-5-(6-methoxypyridin-3-yl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-phenyl-5-(thiophen-2-yl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-phenyl-5-(thiophen-3-yl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-5-(3-methyloxazol-5-yl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-5-(4-trifluoromethylphenyl)-4-hydroxy-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-5-(4-fluorophenyl)-4-hydroxy-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-5-(4-chlorophenyl)-4-hydroxy-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-5-(4-methylphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-5-(3-fluorophenyl)-4-hydroxy-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-5-(3-methylphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-5-(3,4-dimethoxyphenyl)-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-3-(4-chlorophenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(naphth-1-yl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-3-(4-ethylphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-[4-(1-methylethyl)phenyl]-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-5-phenyl-3-(4-propylphenyl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(1-hydroxy-5-chloronaphth-2-yl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-5-(4-fluorophenyl)-4-hydroxy-3-(1-hydroxynaphth-2-yl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(1-hydroxynaphth-2-yl)-5-(4-methylphenyl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-3-(4-fluoro-2-methoxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(5-fluoro-2-methoxyphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(3,4-dimethoxyphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,3-[2-chloro-4-hydroxy-3-(2-hydroxy-4-methylphenyl)-6-oxo-6,7-dihydro-thieno[2,3-b]pyridin-5-yl]-benzoicacid,2-chloro-3-(4,5-difluoro-2-hydroxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(2-hydroxy-4-methylphenyl)-5-(4-methylphenyl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(2-hydroxy-4-methylphenyl)-5-(pyridin-3-yl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(3,4-dimethylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-3-(3-fluoro-4-methyl-2-methoxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(2-methoxy-3,4-dimethylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(2-hydroxy-3,4-dimethylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-3-(4-fluorophenyl)-5-(4-fluorophenyl)-4-hydroxy-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-3-(3-fluoro-2-hydroxy-4-methylphenyl)-5-(4-fluorophenyl)-4-hydroxy-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(2-hydroxy-4,5-dimethylphenylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-3-(3,4-difluoro-2-hydroxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-3-(4-ethyl-2-hydroxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-3-(3-fluoro-2-hydroxy-4-methylphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-fluoro-3-(3-fluoro-2-hydroxy-4-methylphenyl)-5-(4-fluorophenyl)-4-hydroxy-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-3-(4-fluoro-2-hydroxyphenyl)-4-hydroxy-5-(4-methoxyphenyl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-3-(4-fluoro-2-hydroxyphenyl)-5-(4-fluorophenyl)-4-hydroxy-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-3-(4-fluoro-2-hydroxyphenyl)-4-hydroxy-5-(4-methylphenyl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,or a pharmaceutically usable salt or stereoisomer thereof, including amixture of stereoisomers in any ratio.
 9. A compound according to claim1 selected from the following compounds:2-chloro-4-hydroxy-3-(3-hydroxy-4-methylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(3-hydroxy-4-methylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(3-methoxy-4-methylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-3-(5-fluoro-2-hydroxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(4-fluorophenyl)-5-(3-cyanophenyl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(1-hydroxy-naphth-2-yl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,N-methyl-3-(2-chloro-4-hydroxy-5-phenyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridin-3-yl)benzamide,2-chloro-3-(4,5-difluoro-2-hydroxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(2-hydroxy-3,4-dimethylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-3-(3-fluoro-2-hydroxy-4-methylphenyl)-5-(4-fluorophenyl)-4-hydroxy-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-4-hydroxy-3-(2-hydroxy-4,5-dimethylphenylphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-3-(3,4-difluoro-2-hydroxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-3-(4-ethyl-2-hydroxyphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-3-(3-fluoro-2-hydroxy-4-methylphenyl)-4-hydroxy-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one,2-chloro-3-(4-fluoro-2-hydroxyphenyl)-4-hydroxy-5-(4-methoxyphenyl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one,or a pharmaceutically usable salt or stereoisomer thereof, including amixture of stereoisomers in any ratio.
 10. A process for the preparationof a compound of the formula (I) according to claim 1 or apharmaceutically usable salt or stereoisomer thereof, comprising:cyclizing a compound of the formula (II)

wherein R¹, R², R³ have the meanings indicated in claim 1, and ALKdenotes C₁-C₆ alkyl under basic conditions, and/or converting a base oracid of the formula I into one of its salts.
 11. A medicamentcomposition comprising at least one compound of formula (I) of claim 1,and/or a pharmaceutically usable salt or stereoisomer thereof, includinga mixture of stereoisomers in any ratio, and at least one excipient oradjuvant.
 12. A method for direct AMPK activation, comprisingadministering to a subject in need thereof an effective amount of thecompound of claim
 1. 13. A method for increasing the uptake of glucosein muscular cells, comprising administering to a subject in need thereofan effective amount of the compound of claim
 1. 14. A compound accordingto claim 4, in which Het denotes pyridyl, pyrimidinyl, furanyl,isoxazolyl, imidazolyl, pyrazolyl, oxazolyl, pyrrolyl, thiazolyl,isothiazolyl, thienyl, triazolyl, tetrazolyl, indolyl, benzimidazolyl orindazolyl, or a pharmaceutically usable salt or stereoisomer thereof,including a mixture of stereoisomers in any ratio.